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Importance No effective treatments are currently available for severe tinnitus, which affects 1% of the population and lowers the quality of life. The factors that contribute to the transition from mild to severe tinnitus are poorly known. Before performing genetic analyses and determining the mechanisms involved in the development of severe tinnitus, its heritability needs to be determined. Objectives To examine whether clinically significant tinnitus is associated with genetic factors and to evaluate the genetic risk in the transmission of tinnitus using adoptees. Design, Setting, and Participants Data from adoptees and their biological and adoptive parents from Swedish nationwide registers were collected from January 1, 1964, to December 31, 2015, and used to separate genetic from environmental factors in familial clustering. In all, 11 060 adoptees, 19 015 adoptive parents, and 17 025 biological parents were investigated. The study used a cohort design and a case-control approach to study genetic and nongenetic factors in tinnitus among adoptees. Main Outcomes and Measures The primary outcome was odds ratio (OR) of tinnitus in adoptees with at least 1 affected biological parent compared with adoptees without any affected biological parent using logistic regression. The secondary outcome was OR in adoptees with at least 1 affected adoptive parent compared with adoptees without any affected adoptive parent. Results A total of 1029 patients (440 [42.8%] male; mean [SD] age, 62 [14] years) with tinnitus were identified. The prevalence of diagnosed tinnitus was 2.2%. The OR for tinnitus was 2.22 for adoptees (95% CI, 1.03-4.81) of biological parents diagnosed with tinnitus, whereas the OR was 1.00 (95% CI, 0.43-2.32) for adoptees from adoptive parents diagnosed with tinnitus. Mean (SE) heritability determined using tetrachoric correlations was 31% (14%). Conclusions and Relevance The findings suggest that genetic factors are associated with the familial clustering of clinically significant tinnitus with no shared-environment association, revealing that the transition from negligible to severe tinnitus may be associated with genetic factors. These findings may provide insight for future genetic analyses that focus on severe tinnitus.
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Association of Genetic vs Environmental Factors in Swedish
Adoptees With Clinically Significant Tinnitus
Christopher R. Cederroth, PhD; MirNabi PirouziFard, PhD; Natalia Trpchevska, MD; Esma Idrizbegovic, MD, PhD;
Barbara Canlon, PhD; Jan Sundquist, MD, PhD; Kristina Sundquist, MD, PhD; Bengt Zöller, MD, PhD
IMPORTANCE No effective treatments are currently available for severe tinnitus, which affects
1% of the population and lowers the quality of life. The factors that contribute to the
transition from mild to severe tinnitus are poorly known. Before performing genetic analyses
and determining the mechanisms involved in the development of severe tinnitus, its
heritability needs to be determined.
OBJECTIVES To examine whether clinically significant tinnitus is associated with genetic
factors and to evaluate the genetic risk in the transmission of tinnitus using adoptees.
DESIGN, SETTING, AND PARTICIPANTS Data from adoptees and their biological and adoptive
parents from Swedish nationwide registers were collected from January 1, 1964, to December
31, 2015, and used to separate genetic from environmental factors in familial clustering. In all,
11 060 adoptees, 19 015 adoptive parents, and 17 025 biological parents were investigated.
The study used a cohort design and a case-control approach to study genetic and nongenetic
factors in tinnitus among adoptees.
MAIN OUTCOMES AND MEASURES The primary outcome was odds ratio (OR) of tinnitus in
adoptees with at least 1 affected biological parent compared with adoptees without any
affected biological parent using logistic regression. The secondary outcome was OR in
adoptees with at least 1 affected adoptive parent compared with adoptees without any
affected adoptive parent.
RESULTS A total of 1029 patients (440 [42.8%] male; mean [SD] age, 62 [14] years) with
tinnitus were identified. The prevalence of diagnosed tinnitus was 2.2%. The OR for tinnitus
was 2.22 for adoptees (95% CI, 1.03-4.81) of biological parents diagnosed with tinnitus,
whereas the OR was 1.00 (95% CI, 0.43-2.32) for adoptees from adoptive parents diagnosed
with tinnitus. Mean (SE) heritability determined using tetrachoric correlations was 31% (14%).
CONCLUSIONS AND RELEVANCE The findings suggest that genetic factors are associated with
the familial clustering of clinically significant tinnitus with no shared-environment association,
revealing that the transition from negligible to severe tinnitus may be associated with genetic
factors. These findings may provide insight for future genetic analyses that focus on severe
tinnitus.
JAMA Otolaryngol Head Neck Surg. doi:10.1001/jamaoto.2018.3852
Published online January 17,2019.
Invited Commentary
Author Audio Interview
Supplemental content
Author Affiliations: Department of
Physiology and Pharmacology,
Karolinska Institutet, Stockholm,
Sweden (Cederroth, Trpchevska,
Canlon); Centre for Primary Health
Care Research, Department of Clinical
Sciences, Malmö, Lund University,
Malmö, Sweden (PirouziFard,
J. Sundquist, K. Sundquist, Zöller);
Hörsel-och Balanskliniken, Karolinska
Universitetssjukhuset, Stockholm,
Sweden (Idrizbegovic).
Corresponding Author: Christopher
R. Cederroth, PhD, Department of
Physiology and Pharmacology,
Karolinska Institutet, Biomedicum,
Solnavägen 9, Stockholm 171 77,
Sweden (christopher.cederroth@ki.
se).
Research
JAMA Otolaryngology–Head & Neck Surgery | Original Investigation
(Reprinted) E1
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Tinnitus is one of the most prevalent and distressing
symptoms associated with hearing loss. It is defined by
the perception of sounds despite their physical ab-
sence (the phantom perception of sounds).
1
This auditory con-
dition affects more than 15% of the population worldwide (an
estimated 70 million people in Europe). In 1 to 2 of 10 people,
tinnitus becomes a chronic bothersome and incapacitating
symptom,
2,3
with highly unmet clinical needs.
4
The psycho-
logical consequences of tinnitus affect the economy by influ-
encing work and sleep and increasing the risk of sick leave and
disability pension.
5
Tinnitus is a complex and heterogeneous auditory dys-
function with numerous causes and phenotypes.
6
It is fre-
quently associated with hearing problems and noise exposure,
7
but it also occurs in humans with normal hearing.
8
The cur-
rent models stipulate that tinnitus mimics the processes of
phantom limb perception,
9
whereby the loss of sensory in-
put (most often by sensory deafferentation) leads to compen-
satory mechanisms in the brain that cause the false sensation
of a missing limb or sounds.
8
This phenomenon of maladap-
tive plasticity in the presence of deafferentation appears as a
common denominator of most forms of phantom percepts in
the absence of sensory stimuli.
10
In the context of tinnitus, this
translates into greater neuronal activity (centralgain) along the
auditory pathway.
11
Although depression covaries with tinni-
tus prevalence and severity over time,
12
clinically significant
anxiety and stress appear as a predominant emotional
comorbidity.
13
Limbic structures have been implicated in tin-
nitus in humans
14,15
and in animal models,
16
suggesting that
central regions involved in emotional processing and cogni-
tion could contribute to tinnitus
17
and more potentially to its
severity.
For decades, it has been widely believed that tinnitus is a
consequence of environmental factors (as opposed to genetic
factors, reviewed by Vona et al
18
). One familial aggregations
study
19
found no obvious correlation in siblings (0.16%);geno-
type candidate genes in patients with tinnitus failed to reveal
positive associations,
20-24
and a recent genome-wide associa-
tion study
25
with a small sample size found no significant as-
sociations. A twin study
26
revealed a heritability of 0.40 based
on self-reported tinnitus. It has been proposed that the lack
of evidence on a significant association with genetic factors
is attributable to the large heterogeneity of tinnitus and that
tinnitus should not be considered a single entity but an en-
semble of multiple subtypes.
27
In support of this hypothesis,
Maas et al
28
recently found that specific forms of tinnitus had
greater heritability in a sex-specific manner. When consider-
ing tinnitus perceived in 2 ears (bilateral), heritability reached
0.41 in women and 0.68 in men.
28
In contrast, when tinnitus
was heard in only 1 ear (unilateral), heritability decreased to
near 0.27. However, 3 major limitations appear from these re-
ports: (1) the sparse data could be attributable to tinnitus being
self-reported and prevalence varying depending on how the
question is formulated
29
; (2) self reporting tinnitus could be
affected by shared-environment mechanisms whereby, for in-
stance, a sibling with tinnitus may influence the awareness of
tinnitus in the other or because both siblings live in a noisy en-
vironment; and (3) these studies did not consider tinnitus se-
verity, which could also be associated with genetic factors, as
is the case for other emotional processing disorders.
30
We addressed these issues by performing an adoption
study using national medical registry data (ie, tinnitus has been
diagnosed by a physician) to determine whether shared-
environment mechanisms are associated with the co-
occurrence of tinnitus within a family and thus constitute a
bias in the estimates of heritability.
Methods
Data were collected on adoptees and their biological and adop-
tive parents from January 1, 1964, to December 31, 2015, to de-
termine the heritability of tinnitus. Informed consent was
waived as a requirement by the Ethics Committee atLund Uni-
versity. Accordingly, all data were provided by Statistics Swe-
den and the National Board of Health and Welfare for re-
search purposes. Data were coded according to EuropeanUnion
law. This study was approved by the Regional Ethical Review
Board of Lund University.
We used several Swedish nationwide registers as part of
our analyses. Statistics Sweden and the National Board of
Health and Welfare maintain the registers used in the present
study.
31-34
The Swedish personal identity number is issued to
all residents in Sweden and was used to connect individual-
level data from different registers.
35
The personal identity num-
bers were replaced by Statistics Sweden with serial numbers
to preserve anonymity. We used data from the SwedishMulti-
Generation Register, the National Patient Register (NPR), the
Total Population Register, and Small Area Market Statistics
(SAMS).
The Swedish Multi-Generation Register contains data on
familial relationships, including adoptions. This register com-
prises data on index persons registered in Sweden after 1961
and born during and later than 1932.
31
The NPR
33
contains all
hospital discharge diagnoses for all people in Sweden from 1964
to 2015. The hospital discharge register has nationwide cov-
erage since 1987. The NPR also includes the Hospital Outpa-
tient Register,which contains information on diagnoses from
all hospital outpatient visits in Sweden between 2001 and 2015.
The Primary Healthcare Register, which contains data from
1989 to 2016, was also used.
36
The Total Population Register
contains data on life events, including birth, death, name
change, marital status, family relationships, educational at-
tainment, and migration within Sweden as well as immigra-
Key Points
Question Is clinically significant tinnitus associated with genetic
factors?
Findings In this study of national registry data from 11 060
adoptees, 19 015 adoptive parents, and 17 025 biological parents, a
heritability of 32% and no association of shared environment with
the transmission of tinnitus were found.
Meaning The present study suggests that genetic factors are
associated with the familial clustering of severe tinnitus.
Research Original Investigation Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus
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tion to and emigration from other countries.
32
Nearly 100% of
births and deaths, 95% of immigrations, and 91% of emigra-
tions are reported to the Total Population Register. Starting in
1991, SAMS data were used to define a municipal subarea and
characterize a neighborhood; the code is composed of the
county, municipality, and unique SAMSarea (9200 in the whole
of Sweden).
Definition of Tinnitus and Comorbidities
Patients with tinnitus in the Swedish Hospital Discharge
Register (1964-2015), Outpatient Register (2001-2015), and
Primary Healthcare Register (1997-2015) were identified by
the following International Classification of Diseases (ICD)
codes: ICD-7 code 781.32, ICD-8 code 781.31, ICD-9 code
388D, and ICD-10 code H931. There was no primary care
code that is specific for tinnitus before 1997. The main and
all secondary diagnoses were used. The validity in the Hos-
pital Discharge Register is generally between 85% and
95%.
33
Depression, anxiety, and hearing loss were identified by
ICD codes any time during the 1964 to 2015 follow-up period
using the Swedish Hospital Discharge Register (1964-2015),
Outpatient Register (2001-2015), and Primary Healthcare Reg-
ister (1997-2015). ICD codes are presented in the eTable in the
Supplement.
Sample
The analyses were based on a data set that encompasses all
Swedish-born adoptees (born between 1960 and 1990) and
their biological and adoptive parents. Adoptees were
excluded from the study if they had died before 16 years of
age (ie, exclusion of adoptees with possible severe congeni-
tal diseases or confounding sociodemographic factors that
cause children to be placed in adoptive homes), had
migrated from Sweden before 16 years of age, had died
before 1964 (ie, before start of follow-up), or were not linked
to at least 1 biological and at least 1 adoptive parent.
All adoptees who had cohabited with a biological parent
were excluded according to census data (every fifth year
from 1960 to 1990) or SAMS data (yearly from 1991). Adop-
tees who had lived with their biological grandparent, aunt
and/or uncle, and sibling or with stepparents together with
their biological parent were also excluded. A total of 11060
Swedish-born adoptees remained in the study after exclu-
sions. They compose the study population in the cohort
study. These adoptees could be linked to 19 015 adoptive
parents and 17 025 biological parents. After exclusions, we
identified 1029 patients (2.2%) with tinnitus among adop-
tees and their adoptive and biological parents. Of the 1029
cases of tinnitus, 214 were found in adoptees, 371 in biologi-
cal parents, and 444 in adoptive parents.
Of the 1029 patients with tinnitus, 525 (51.0%) were found
in the Outpatient Register, 23 (2.2%) in the Hospital Dis-
charge Register, and 481 (46.7%) in the Primary Healthcare Reg-
ister through ICD codes. Seven tinnitus cases (0.7%) were iden-
tified with ICD-8 codes and 9 (0.9%) with ICD-9 codes. No
tinnitus case was identified with ICD-7. A total of 1013 tinni-
tus cases (98.4%) were identified with ICD-10 codes.
Educational attainment was categorized into 4 groups: low
(0–9 years), middle (10–11years), high (≥12 years or more), and
unknown.
Statistical Analysis
We used a cohort design and a case-control approach to study
genetic and nongenetic factors associated with tinnitus among
adoptees. We conducted 2 main analyses. Odds ratios (ORs)
were determined with logistic regression for adoptees with an
affected biological parent and for adoptees with an affected
adoptive parent. We used a case-control matching method (1:4)
for sex, educational attainment, county of birth, and ±1 year
for birth year by drawing a sample of tinnitus-affected adop-
tees as patients and matched control groups of tinnitus-
unaffected adoptees.
37,38
In the case-control study, we con-
nected both groups to their biological and adoptive parents,
and ORs were calculated with conditional logistic regression.
In the cohort study, logistic regression was used to deter-
mine crude (crude [univariate] models for each variable; model
1) and multivariate (adjusted model; model 2) ORs for history
of tinnitus in biological or adoptive parents. In the multivar-
iate model (adjusted model 2), we used adoptees’ birth year,
sex, educational attainment, and county of birth as covari-
ates in the cohort study. The primary outcome was OR of tin-
nitus in adoptees with at least 1 affected biological parent com-
pared with adoptees without any affected biological parent.
The secondary outcome was OR in adoptees with at least 1 af-
fected adoptive parent compared with adoptees without any
affected adoptive parent.
An important question in medicine is whether an ob-
served variation in a particular disease is associated with en-
vironmental factors or biological factors (nature vs nurture de-
bate). In genetics, heritability summarizes how heritable a
disease of interest is, that is, the proportion of variance that
emerges because of hereditary factors, especially with refer-
ence to the resemblance of offspring and parents.
Formally, heritability was defined as a ratio of variances,
that is, the proportion of total variance that is associated with
variation in additive genetic factors. According to classic quan-
titative genetics, the heritability of a binary trait (or disease)
could be estimated by Falconerregression or with relatives’ tet-
rachoric correlation by presuming a liability threshold model
of the disease in which everyone has a liability to develop the
disease but only individuals above a threshold value do so.
39-41
To evaluate heritability for tinnitus, 2 different methods
were used. First, we used Falconer regression, which is based
on the liability of the threshold, to obtain heritability in adop-
tees of the biological parents. The method and its application
are described in detail by Falconer and MacKay.
40,41
With use
of the prevalence rate of the relatives of the biological pro-
bands and the controls (ie, biological parents to affected and
unaffected adoptees, respectively) from the case-control study,
the mean (SE) heritability was calculated. Second, we used the
approach described by Frisell et al,
39
which used the tetra-
choric correlation. This method allowed us to test the sensi-
tivity of the calculated heritability to the assumed preva-
lence. The tetrachoric correlation is the inferred Pearson
correlation from a 2 × 2 table with dichotomous normality
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being assumed. We used χ
2
and Wald tests (in logistic regres-
sion). A 2-sided P< .05 was considered to be statistically sig-
nificant. Statistical analysis was performed with SAS soft-
ware, version 9.3 (SAS Institute Inc).
Results
We identified1029 patients (2.2%) w ithtinnitus (440 [42.8%]
male; mean [SD] age, 62 [14] years) in the study populationdur-
ing the study period (1964-2015). Table 1 gives the descrip-
tive statistics of the adopted offspring, their biological par-
ents, and their adoptive parents: age, sex, educational
attainment, tinnitus, age at tinnitus diagnosis, and age at end
of the study period (death, emigration, or end of the study pe-
riod on December 31, 2015, whichever came first). The Figure
shows the age distribution for Swedish-born (1960-1990)adop-
tees at first-time diagnosis of tinnitus. The adoptive parents,
with a median age of 78 years (interquartile range[IQR], 70-83
years), were older than the biological parents, with a median
age of 69 years (IQR, 59-74 years) at the end of the study pe-
riod. Table 1 reports that the median birth years were1965 (IQR,
1962-1970) for adoptees, 1942 (IQR, 1936-1947) for biological
parents, and 1932 (IQR, 1927-1939) for adoptive parents. Tin-
nitus was found in 371 of 17 025 biological parents (2.18%) and
444 of 19 015 adoptive parents (2.33%). No statistically signifi-
cant differences were found between these groups (x
2
=0.99,
P= .32). Tinnitus in adoptees, biological parents, and adop-
tive parents was found to be associated with depression, anxi-
ety,and hearing loss (Table 2). The ORs were 1.89 (95% CI, 1.40-
2.55) for depression, 2.19 (95% CI, 1.67-2.88) for anxiety, and
24.38 (95% CI, 18.08-32.88) for hearing loss using a crude
model.
Cohort Study
In crude model 1 (univariate), the OR for tinnitus in adoptees
with at least 1 affected parent was increased (OR, 1.83; 95% CI,
1.04-3.24) (Table 3). In the fully adjusted model 2 (multivari-
ate), which also included birth year, sex, county, educational
attainment, depression, anxiety, and hearing loss, the famil-
ial OR for tinnitus was still significant at 2.01 (95% CI, 1.10-
3.69). The estimated OR for tinnitus in adoptees with an af-
fected adoptive parent was not statistically significant in the
crude model 1 (univariate) (OR, 1.01; 95% CI, 0.53-1.91) or in
the adjusted model 2 (multivariate) (OR, 1.04; 95% CI, 0.53-
2.04). In a model that included the history of tinnitus in bio-
logical and adoptive parents, 10 179 individuals had no his-
tory of tinnitus in biological and adoptive parents, 498
individuals had adoptive parents only with tinnitus, 368 in-
dividuals had biological parents only with tinnitus, and 15 in-
dividuals had both biological and adoptive parents with his-
tory of tinnitus (interaction term Waldχ
2
= 0.0011; SE = 351.6).
Case-Control Study
We further validatedthese findings using a case-control study.
Tinnitus in adoptees was significantly associated with tinni-
tus in biological parents, with an OR of 2.22 (95% CI, 1.03–
4.81) for the 10 adoptees with an affected biological parent com-
pared with the 136 adoptees with unaffected biological parents.
Tinnitus in an adoptive parent was not significantly associ-
ated with tinnitus in adoptees (7 adoptees with an affected
adoptive parent vs 139 with no affected adoptive parent; OR,
1.00; 95% CI, 0.43–2.32). These findings suggest that genetic
factors are associated with the transmission of clinically sig-
Table 1. Characteristics of the Study Populationof Swedish-Born Adoptees
Between 1960 and 1990 and Their Adoptive and Biological Parents
Characteristic
Adopted Offspring
(n = 11 060)
Adoptive Parents
(n = 19 015)
Biological Parents
(n = 17 025)
Female 5213 (47.13) 9505 (49.99) 10 358 (60.84)
Age at end of follow-up, median
(IQR), y
50 (44-52) 78 (70-83) 69 (59-74)
Birth year
Mean (SD) 1967 (7) 1933 (9) 1941 (10)
Median (IQR) 1965 (1962-1970) 1932 (1927-1939) 1942 (1936-1947)
Range 1960-1990 1888-1972 1898-1974
High educational attainment (≥12
y)
3450 (31.19) 4202 (22.10) 1452 (8.37)
Tinnitus cases 214 (1.93) 444 (2.33) 371 (2.18)
Female patients with tinnitus 113 (52.80) 244 (54.95) 232 (62.53)
Age at tinnitus diagnosis, median
(IQR), y
43 (38-47) 71 (63-77) 65 (60-70)
Abbreviation: IQR, interquartile
range.
a
Data are presented as number
(percentage) of population unless
otherwise indicated. The numbers
of parents represent unique
individuals. Some parents had
several biological or adoptive
children.
Figure. Age Distribution for Swedish-Born (1960-1990) Adoptees
When Tinnitus Was First Diagnosed
0
30
25
Adoptees, %
20
15
10
5
Age of Adopted-Away Offspring at the First Diagnosis, y
10 15 20 25 30 35 40 45 50 55 60 65
Research Original Investigation Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus
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nificant tinnitus and that there is no association of shared en-
vironment with the transmission of tinnitus.
Heritability
Heritability was determined in the case-control study with dif-
ferent estimates of the prevalence of tinnitus (Table 4). The
prevalence in the particular source population is unknown;
however,on the basis of a previous systematic review,
29
a range
of likely estimates was selected. The corresponding range of
heritability estimates is presented in Table 4. The heritability
varied from 19% in a population with 0.01% prevalenceto 35%
in a population with 5% prevalence. With a prevalence of 2.0%
(Table 4) in the present population, the mean (SE) heritability
was 31% (14%). This finding is similar to the heritability ob-
tained using Falconer regression. The mean (SE) heritability
determined using Falconer regression was 32.3% (15.7%).
Discussion
This study identified an association between tinnitus and adop-
tees in relation to their biological parents but not to their adop-
tive parents. In other words, tinnitus in adoptive parents did
not increase the odds of tinnitus among adoptees, a finding
that suggests a limited association of family-related environ-
mental factors with the heritability of tinnitus. Adoption stud-
ies are complementary to twin studies for a number of rea-
sons. It is assumed in twin studies that concordance rates
Table 2. Prevalenceof Hearing Loss, Depression, and Anxiety Among Study Participants
With and Without Tinnitus Any Time During Follow-up(1964-2015)
Variable
No. (%) of Study Participants
PValue
a
No Tinnitus Tinnitus
Adoptees
No. 10 846 214 NA
Depression 1927 (17.8) 62 (30.0) <.001
Anxiety 2938 (27.1) 97 (45.3) <.001
Hearing loss 310 (2.9) 97 (45.3) <.001
Adoptive Parents
No. 18 571 444 NA
Depression 1978 (10.6) 89 (20.0) <.001
Anxiety 1943 (10.5) 111 (25.0) <.001
Hearing loss 2 289 (12.3) 276 (62.2) <.001
Biological Parents
No. 16 654 371 NA
Depression 2194 (13.2) 92 (24.8) <.001
Anxiety 3116 (18.7) 120 (32.2) <.001
Hearing loss 1064 (6.4) 194 (52.3) <.001
Abbreviation: NA, not applicable.
a
χ
2
Tes t.
Table 3. Risk of Tinnitusin Adoptees as Determined by Affected Biological or Adoptive Parent (Cohort Study)
Variable
No. of
Person-
Years
Cases/Persons at
Risk
Incidence Rate per 1000
Person-Years Incidence Ratio (95% CI)
OR (95% CI)
a
Model 1 Model 2
Risk of tinnitus
with at least 1
affected biological
parent
Biological
parents not
affected
b
495 278 201/10677 0.41 (0.35-0.46) NA NA NA
Biological
parent affected
18 122 13/383 0.72 (0.42-1.24) 1.77 (1.01-3.10) 1.83 (1.04-3.24) 2.01 (1.10-3.69)
Risk of tinnitus
with at least 1
affected adoptive
parent
Adoptive
parents not
affected
b
490 606 204/10 547 0.42 (0.36-0.48) NA NA NA
Adoptive parent
affected
22 794 10/513 0.44 (0.24-0.82) 1.06 (0.56-1.99) 1.01 (0.53-1.91) 1.04 (0.53-2.04)
Abbreviations: NA, not applicable; OR, odds ratio.
a
The ORs were derived from unconditional logistic regression. Model 1 is a
crude model (univariate). Model 2 is an adjusted model (multivariate), with
adjustments for adoptees’ birth year,sex, county, educational attainment,
depression, anxiety, and hearing loss.
b
Reference group.
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between monozygotic and dizygotictw ins are comparable and
can thus be used to estimate genetic contributions because the
twins share the same environment. However, one study
42
sug-
gests that monozygotic twins are treated more equally than di-
zygotic twins, which in theory would inflate the heritability
seen in twin studies. Whether violation of the equal environ-
ments assumption in twin studies for tinnitus affects esti-
mates of heritability is not known. It is also not known whether
the assumption of random mating affects the estimates of tin-
nitus heritability. Because adoptees do not grow up in their bio-
logical families, adoption studies offer an excellent model to
investigate genetic influences of a given trait. Transmission
from adoptive parents to nonbiological offspring would be
mainly associated with environmental factors, whereas the
transmission from biological parents to offspring would there-
fore be associated with genetic factors. However, although this
notion is important to understand the transmission of tinni-
tus, the present work cannot completely rule out the contri-
bution of shared environment in tinnitus development. In this
study, most adoptees were diagnosed with tinnitus in adult-
hood, and whether familial environmental factors are weak-
ened or not after adoptees become adults remains uncertain.
Familial aggregation studies, including influence on spouses,
may help complement the present study;however, one should
consider that different mechanisms of development of se-
vere tinnitus may occur between men and women, as re-
cently suggested.
13
Strengths and Limitations
A major strength in the present study is the use of nationwide
registers, which are almost complete and have successfully
been used to estimate familial risks for a number of
diseases.
31-34,36,43
Moreover, the study design eliminates the
risk of recall bias, which is an important problem in case-
control studies. Wereveal a heritability of 32%, which is in the
range of the values that 2 former Swedish twin studies re-
ported (near 40% for any type of tinnitus).
26,28
The study from
Bogo et al
26
used a sample of twins (n = 1084 individuals)
whose pure-tone audiometric thresholds (up to 8 kHz) were
available, whereas the study from Maas et al
28
estimated heri-
tability on a larger sample size (n = 10 464 twin pairs) in the
absence of audiometric data. These 2 twin studies
26,28
relied
on self-reported tinnitus, which does not specify the degree
of severity, the duration (acute vs chronic), and the time com-
ponent (occasional vs permanent). In addition, the way that
the question was formulated may cause substantial differ-
ences in the reported prevalence,
29
which in turn can affect
heritability values. In this study, heritability values were ob-
tained using medical registries based on a diagnostic estab-
lished by a physician, which may be seen as a more rigorous
approach, although not free from biases. The prevalence of 2%
appears on the low side of the mean prevalence of self-
reported severe tinnitus in the literature.
29
The number of
people with tinnitus seeking help may be lower in this study
because of the general lack of trust in the ability of physicians
to provide a solution to their tinnitus.
44
Because heritability
values are influenced by prevalence, the values obtained in our
study were potentially underestimated. Tinnitus assessment
and treatment are not standardized at the nationallevel in Swe-
den; however, the Stockholm County Council has developed
a document to guide the assessment of tinnitus at the general
practitioner level using the Tinnitus Handicap Inventory and
proposed some rehabilitation options, such as cognitive be-
havioral therapy and a modified tinnitus retraining therapy.
A patient is directed for special rehabilitation when the Tin-
nitus Handicap Inventory score is 58 or higher (meaning se-
vere or catastrophic) or when clinically significant levels of
anxiety or depression are found. How tinnitus assessment and
rehabilitation are performed in other counties is unclear, and
therefore the global picture of tinnitus care in Sweden is miss-
ing. Thus, the country would benefit from national tinnitus
guidelines,
45
which would harmonize the reporting proce-
dures and national registry data. The problem of the clinical
assessment of tinnitus is not restricted to Sweden because of
the disparity in assessing tinnitus if found across all Euro-
pean Union countries (Cederroth et al, unpublished data, 2017),
which emphasizes the need to standardize its clinical assess-
ment until objective tools can be implemented in the health
care system.
Assuming that occasional tinnitus precedes the develop-
ment of permanent tinnitus and mild tinnitus also precedes
the development of severe tinnitus would mean that the cur-
rent study using medical registries, in which a diagnosis is re-
ported, would underestimate the heritability values by focus-
ing only on clinically significant tinnitus. A focus on severe
tinnitus may reveal heritability values that would not be di-
rectly associated with the development of tinnitus per se; in-
stead, these values would be more associated with the accom-
panying psychological distress. Whereas none of the
investigated polymorphisms have been associated with tin-
nitus (using a group without tinnitus as controls), a variant in
the promoter of the serotonin transporter gene (SLC6A4)
(OMIM 182138) was associated with tinnitus severity when
compared with patients with milder tinnitus.
46
Similarly,a pi-
lot genome-wide association study
25
with a small sample size
of 167 patients and 769 controls found no significant associa-
tions but revealed an enrichment in genes involved in seroto-
nin receptor signaling. These studies are consistent with re-
Table 4.Heritability of Tinnitus Based on Different Estimated Population
Prevalence and Tetrachoric Correlation in the Case-Control Study
a
Prevalence
Tetrachoric
Correlation, Mean
(SE) Heritability, Mean (SE), %
0.01 0.094 (0.04) 19 (8)
0.05 0.105 (0.05) 21 (10)
0.1 0.11 (0.05) 22 (10)
0.5 0.13 (0.06) 26 (12)
1.0 0.14 (0.06) 28 (12)
2.0 0.153 (0.07) 31 (14)
5.0 0.174 (0.08) 35 (16)
Abbreviation: OR, odd ratio.
a
Based on Frisell et al.
39
There were 10 exposed patients (adoptees with
tinnitus and an affected biological parent) and 136 unexposed patients
(adoptees with tinnitus without an affected adoptive parent). The OR was
2.22 (95% CI, 1.03-4.81) for all.
Research Original Investigation Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus
E6 JAMA Otolaryngology–Head & Neck Surgery Published online January 17, 2019 (Reprinted) jamaotolaryngology.com
Downloaded From: on 01/17/2019
cent findings in mice whereby serotonin wouldexcite fusiform
cells from the dorsal cochlear nucleus,
47
a structure from the
auditory pathway known to be involved in tinnitus.
35,48-50
Thus, the heritability values collected in our study may re-
flect the genetic heritability of severe tinnitus and not that of
any type of tinnitus.
A study from Martinez et al
51
suggests that the existing ICD
codes are of sufficient quality for research in a clinical set-
ting. However, we believe that the existing ICD codes for tin-
nitus are obsolete, even when considering ICD codes for hear-
ing loss, and would still benefit from a global revision. Laterality
(meaning whether tinnitus is perceived unilaterally or bilat-
erally) appears as an important classification for genetic sub-
types of tinnitus according to a recent twin study.
28
Maas et al
28
found that bilateral tinnitus is significantly influenced by ge-
netic factors, whereas unilateral tinnitus is more subject to en-
vironmental influences. However, the degree of hearing loss
in patients with unilateral and bilateral tinnitus appears to be
similar (Cederroth et al, unpublished data, 2018), and thus the
establishment of laterality using audiologic register data may
not help in distinguishing patients with bilateral from those
with unilateral tinnitus. Furthermore, although hearing loss
and noise exposure are major etiologic factors for tinnitus, a
nonnegligible proportion of patients experience tinnitus with-
out hearing loss, supporting the notion that the current codes
for tinnitus or hearing loss would not facilitate the replica-
tion of the study by Maas et al.
8
A revision of the ICD codes
for tinnitus is an endeavor that will require substantial evi-
dence to classify tinnitus subtypes according to clear criteria.
Fortunately, temporary ICD codes can be generated for re-
search purposes at a national level and may help determine
whether a newly proposed definition has clinical value be-
fore its implementation into the World Health Organization
codes. Nevertheless, the consistency among these 3 studies in
Sweden supports the idea that some forms of tinnitus are as-
sociated with genetics more than with shared environment.
How this applies to other countries needs to be determined
using similar approaches.
Although it is likely that most adoptions occurred in early
childhood, we lack information regarding the ageat which chil-
dren were adopted. Perinatal factors and preplacement age
could confound the genetic component. In previous studies,
52
most children were adopted before 12 months of age. An-
other limitation is demographic differences between biologi-
cal and adoptive parents. For instance, biological parents (in-
cluding biological parents with tinnitus) were more often
women than adoptive parents. Biological parents (including
biological parents with tinnitus) were also younger than adop-
tive parents. In addition, the present adoption study in-
cluded only adoptees who were born in Sweden; therefore, we
cannot generalize the present study to a population of non-
white origin.
Conclusions
This adoption study using national registry data suggests that
clinically significant tinnitus is associated with genetic fac-
tors, with a heritability of 32% and that there is no associa-
tion between shared-environment factors with the transmis-
sion of tinnitus. Because patients in Sweden with a diagnosis
of tinnitus most often have severe tinnitus, the present data
reveal that there could be an association between genetic fac-
tors and the transition from compensated to decompensated
tinnitus. Thus, the association of genetics with tinnitus might
be found on 2 levels: (1) for determining whether an indi-
vidual develops tinnitus or not and (2) for determining whether
an individual transitions from having nonbothersome tinni-
tus to bothersome tinnitus. The identification of genes in-
volved in any of these 2 aspects may provide interesting in-
sights into the molecular mechanisms that regulate phantom
percepts and their treatment.
ARTICLE INFORMATION
Accepted for Publication: November 9,2019.
Published Online: January 17,2019.
doi:10.1001/jamaoto.2018.3852
Open Access: This is an open access article
distributed under the terms of the CC-BY License.
© 2019 Cederroth CR et al. JAMA Otolaryngology.
Author Contributions: Drs PirouziFard and Zöller
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Cederroth, PirouziFard,
Trpchevska, Idrizbegovic, J. Sundquist, K.
Sundquist, Zöller.
Acquisition, analysis, or interpretation of data:
Cederroth, PirouziFard, Canlon, K. Sundquist, Zöller.
Drafting of the manuscript: Cederroth, PirouziFard,
Trpchevska, Idrizbegovic, Canlon.
Critical revision of the manuscript for important
intellectual content: Cederroth, PirouziFard,
Trpchevska, Canlon, J. Sundquist, K. Sundquist,
Zöller.
Statistical analysis: PirouziFard, Canlon, Zöller.
Obtained funding: Cederroth, Canlon, J. Sundquist,
K. Sundquist, Zöller.
Administrative, technical, or material support:
Trpchevska, J. Sundquist, K. Sundquist.
Supervision: Cederroth, K. Sundquist, Zöller.
Conflict of Interest Disclosures: Dr Cederroth
reported having received consulting fees from
Sensorion Pharmaceuticals. No other disclosures
were reported.
Funding/Support: This study was supported by
grant K2014 99X 22478 01 3 from the Swedish
Medical Research Council (Dr Canlon), Karolinska
Institute (Dr Cederroth), TystaSkolan (Drs
Cederroth and Canlon), grant SLS-779681 from
Svenska Läkaresällskapet (Dr Cederroth), grant 503
from Hörselforskningsfonden (Dr Cederroth), Marie
Skłodowska-Curie grant agreement 72204655 from
the European Union’s Horizon 2020research and
innovation program (Dr Cederroth), Decibel
Therapeutics Inc (Dr Cederroth), Avtal om
Läkarutbildning och forskning funding (Drs J.
Sundquist, K. Sundquist, and Zöller), and the
Swedish Heart-Lung Foundation (Dr Zöller).
Role of the Funder/Sponsor:The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
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Research Original Investigation Association of Genetic vs Environmental Factors in Swedish Adoptees With Clinically Significant Tinnitus
E8 JAMAOtolaryngology–Head & Neck Surgery Published online January 17, 2019 (Reprinted) jamaotolaryngology.com
Downloaded From: on 01/17/2019
... individuals with higher genetic relatedness. Both types have yielded evidence that tinnitus is a heritable condition, though at relatively low to moderate rates [12][13][14][15] . Additionally, Bogo et al. 2017 found that while genetic influences accounted for approximately 40% of phenotypic variation in tinnitus, environment likely plays a large role in determining tinnitus onset and severity. ...
... Additionally, Bogo et al. 2017 found that while genetic influences accounted for approximately 40% of phenotypic variation in tinnitus, environment likely plays a large role in determining tinnitus onset and severity. Alternatively, Cederroth et al. 2019 found that adopted individuals with biological parents affected by tinnitus had a significantly higher odds ratio than those individuals without biological parents with tinnitus, implying a genetic foundation to tinnitus (OR biological = 1.10 < 2.01 < 3.69 vs. OR adoptive = 0.53 < 1.04 < 2.04, 95% CI). The combined results of these types of studies indicate that the predisposition to develop tinnitus may lie within an individual's genes, but other factors likely play key roles in actually inducing the condition. ...
Article
Full-text available
Tinnitus, the phantom perception of noise originating from the inner ear, has been reported by 15% of the world’s population, with many patients reporting major deficits to cognition and mood. However, both objective diagnostic tools and targeted therapeutic strategies have yet to be established. To better understand the underlying genes that may preclude tinnitus, we performed a genome-wide association study of the UK Biobank’s 49,960 whole exome sequencing participants to identify any loci strongly associated with tinnitus. We identified 17 suggestive single nucleotide polymorphisms (p < 1e−5) spanning 13 genes in two sex-separated cohorts reporting chronic, bothersome tinnitus (control males n = 7,315, tinnitus males n = 226, control females n = 11,732, tinnitus females n = 300). We also found a significant missense mutation in WDPCP (p = 3.959e−10) in the female cohort, a mutation which has been previously implicated in typical neuronal functioning through axonal migration and structural reinforcement, as well as in Bardet-Biedl syndrome-15, a ciliopathy. Additionally, in situ hybridization in the embryonic and P56 mouse brain demonstrated that the majority of these genes are expressed within the dorsal cochlear nucleus, the region of the brain theorized to initially induce tinnitus. Further RT-qPCR and RNAScope data also reveals this expression pattern. The results of this study indicate that predisposition to tinnitus may span across multiple genomic loci and be established by weakened neuronal circuitry and maladaptive cytoskeletal modifications within the dorsal cochlear nucleus.
... Tinnitus is a highly heterogeneous condition in humans 775 (Cederroth et al., 2019), and the underlying pathophysio-776 logical mechanisms remain unclear. Recent evidence in 777 animals and humans cumulate towards the involvement of 778 the limbic system in tinnitus (Chen et al., 2015), however 779 the confounding effects of hearing loss and hyperacusis 780 make the disentangling of each contributing factor on the 781 outcomes quite challenging (Khan et al., 2021). ...
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Aims/Hypothesis Tinnitus is a phantom sound perception affecting both auditory and limbic structures. The mechanisms of tinnitus remain unclear and it is debatable whether tinnitus alters attention to sound and the ability to inhibit repetitive sounds, a phenomenon also known as auditory gating. Methods 22 male C57BL/6J mice were used in this study. Anesthetized mice were exposed to a 9-11 kHz narrow band noise (90 dBSPL for 1 hr) and sham exposed mice were used as controls. Hearing thresholds were measured using auditory brainstem responses (ABRs) and tinnitus was assessed using Gap prepulse inhibition of acoustic startle (GPIAS). After the induction of tinnitus, mice were implanted multi-electrodes to assess auditory event-related potentials (aERPs) in the dorsal hippocampus in response to paired clicks. Alterations of aERPs under nicotine (1.0 mg/kg, intraperitoneal (i.p.) or cannabis extract (100 mg/Kg, i.p.) were evaluated (in isolation or in combination), the latter containing 47.25 mg/kg of tetrahydrocannabinol (THC); 0.43 mg/kg of cannabidiol (CBD) and 1.17 mg/kg of cannabinol (CBN), as analyzed by high-performance liquid chromatography (HPLC). Saline-treated animals were used as controls. Results Our results show that mice with behavioral evidence of tinnitus display auditory gating of repetitive click, but with larger amplitudes and longer latencies of the N40 component. In contrast, no difference was observed in the P80 amplitude and latency between groups or treatments. The combination of cannabis extract and nicotine also improved auditory gating ratio in mice with noise-induced tinnitus without permanent hearing threshold shifts by strongly increasing the first N40 click amplitude but without altering the second click response amplitude. Furthermore, the increased latency of the N40 component suggests altered temporal processing of triggered attention in mice with tinnitus due to an increased sensitivity to the exposure to cannabis extract. Conclusion/Interpretation In summary, we show that nicotine and cannabis extract alter sensory gating in mice with behavioral evidence of tinnitus and propose that the altered central plasticity in tinnitus is more sensitive to the combined actions on the cholinergic and the endocannabinoid systems. We conclude that the limbic system may play a role in the altered sensory gating responses on tinnitus since the hippocampus responses to auditory inputs are altered. These findings could enable a new understanding of which neuronal pathways could be involved in sensory gating in tinnitus.
... By considering sex-specific factors, another study identified a greater heritability in male individuals (0.68) compared with female individuals (0.41) with bilateral tinnitus [27]. As twin studies introduce bias owing to shared-environment effects, an adoption study was performed using medical registry data to determine whether a shared environment is associated with tinnitus [28]. The authors uncovered a familial transmission of clinically significant tinnitus with respect to adoptees relative to their biological parents but not adoptive parents and calculated a heritability of 0.32, suggesting a limited association of shared environmental effects with tinnitus heritability. ...
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The feasibility to unravel genetic and genomic signatures for disorders affecting the auditory system has accelerated since arriving in the post-genomics era roughly 20 years ago. Newly emerging studies have provided initial landmarks signaling heritability and thus, a genetic link, to severe tinnitus. Tinnitus, the phantom perception of ringing in the ears, is experienced by at least 15% of the adult population and can be extremely disabling. Despite its ubiquity, there is no cure for tinnitus and modalities offering relief are often of limited success. Because tinnitus is frequently reported in patients with acquired conductive or sensorineural hearing impairment, it has been widely accepted that tinnitus is secondary to and a symptom arising from hearing impairment. However, tinnitus has also been identified in the absence of auditory dysfunction and in young individuals, resulting in a debate about its origins. Genetics studies have identified severe tinnitus as a complex disorder arising from gene and environment interactions, refining its classification as a neurological disorder and, in at least a subset of patients, it appears not as a symptom of another health issue. This current opinion summarizes several recent studies that have challenged a long-accepted dogma and postulates how this information could eventually be used in the future to help patients. It is with great hope that this knowledge opens translational paths to provide relief for the many who suffer from the burden of tinnitus on a daily basis.
... Tinnitus is the perception of sounds in the absence of any external sound source. It is a common condition that is experienced by nearly 15% of the population and has been shown to be influenced by not only environmental factors but also genetics (1)(2)(3)(4)(5)(6). For those with severe tinnitus (one out of ten), the significant impact on life quality is accompanied by a high clinically unmet need (7). ...
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Background: The heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures. Methods: Longitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 was used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort. Results: We determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5 for previous tinnitus (sometimes) to 30 for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603, suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brainstem responses (ABRs) from subjects reporting non-tinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared to occasional tinnitus or non-tinnitus. The ABR from occasional tinnitus was indistinguishable from that of the non-tinnitus controls. Conclusions: Our results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit. Trial registration: Not applicableFUNDING. This study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union's Horizon 2020 Grant No. 848261 (UNITI) and No. 722046 (ESIT).
... When disabling and impacting daily functioning, tinnitus is a heterogeneous and complex condition with multiple associated biological, psychological and contextual contributors, which often remain unknown [7]. Moreover, with increasing severity, it appears to segregate in families, suggesting a genetic cause as well [8,9]. The available treatment options are unsatisfactory [10,11]. ...
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Tinnitus disability is a heterogeneous and complex condition, affecting more than 10% and compromising the quality of life of 2% of the population, with multiple contributors, often unknown, and enigmatic pathophysiology. The available treatment options are unsatisfactory, as they can, at best, reduce tinnitus severity, but not eliminate its perception. Given the spread of tinnitus and the lack of a standardized treatment, it is crucial to understand the economic burden of this condition. We conducted a systematic review of the literature on PubMed/MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR) and Google Scholar, in order to identify all the articles published on the economic burden of tinnitus before 1 April 2021 (PROSPERO—International prospective register of systematic reviews—No: CRD42020180438). Out of 273 articles identified through our search strategy, only five articles from studies conducted in the United States of America (USA), the Netherlands and the United Kingdom (UK) provided data on tinnitus’s economic costs. Three studies provided mean annual estimates per patient ranging between EUR 1544 and EUR 3429 for healthcare costs, between EUR 69 and EUR 115 for patient and family costs and between EUR 2565 and EUR 3702 for indirect costs, including productivity loss. The other two studies reported an annual mean cost of EUR 564 per patient for tinnitus-related clinical visits, and total costs of EUR 1388 and EUR 3725 for patients treated with a sound generator and Neuromonics Tinnitus Treatment, respectively. Our comprehensive review shows a gap in the knowledge about the economic burden of tinnitus on healthcare systems, patients and society. The few available studies show considerable expenses due to healthcare and indirect costs, while out-of-pocket costs appear to be less financially burdensome. Comprehensive health economic evaluations are needed to fill the gaps in current knowledge, using a unified method with reliable and standardized tools.
... Heritability was 56% for bilateral tinnitus compared to 27% for unilateral tinnitus and further stratification by sex showed an increased heritability for males (68%). Additionally, a study on Swedish adoptees with clinically significant tinnitus showed that the shared environment was not associated with tinnitus presence (Cederroth et al., 2019b). ...
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Tinnitus can be a burdensome condition on both individual and societal levels. Many aspects of this condition remain elusive, including its underlying mechanisms, ultimately hindering the development of a cure. Interdisciplinary approaches are required to overcome long-established research challenges. This review summarizes current knowledge in various tinnitus-relevant research fields including tinnitus generating mechanisms, heterogeneity, epidemiology, assessment, and treatment development, in an effort to highlight the main challenges and provide suggestions for future research to overcome them. Four common themes across different areas were identified as future research direction: 1. Further establishment of multicenter and multidisciplinary collaborations; 2. Systematic reviews and syntheses of existing knowledge; 3. Standardization of research methods including tinnitus assessment, data acquisition, and data analysis protocols; 4. The design of studies with large sample sizes and the creation of large tinnitus-specific databases that would allow in-depth exploration of tinnitus heterogeneity.
Article
Importance: To date, no systematic review has taken a meta-analytic approach to estimating the prevalence and incidence of tinnitus in the general population. Objective: To provide frequency estimates of tinnitus worldwide. Data sources: An umbrella review followed by a traditional systematic review was performed by searching PubMed-MEDLINE and Embase from inception through November 19, 2021. Study selection: Research data from the general population were selected, and studies based on patients or on subgroups of the population with selected lifestyle habits were excluded. No restrictions were applied according to date, age, sex, and country. Data extraction and synthesis: Relevant extracted information included type of study, time and location, end point, population characteristics, and tinnitus definition. The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main outcomes and measures: Pooled prevalence estimates of any tinnitus, severe tinnitus, chronic tinnitus, and diagnosed tinnitus as well as incidence of tinnitus were obtained using random-effects meta-analytic models; heterogeneity between studies was controlled using the χ2 test, and inconsistency was measured using the I2 statistic. Results: Among 767 publications, 113 eligible articles published between 1972 and 2021 were identified, and prevalence estimates from 83 articles and incidence estimates from 12 articles were extracted. The pooled prevalence of any tinnitus among adults was 14.4% (95% CI, 12.6%-16.5%) and ranged from 4.1% (95% CI, 3.7%-4.4%) to 37.2% (95% CI, 34.6%-39.9%). Prevalence estimates did not significantly differ by sex (14.1% [95% CI, 11.6%-17.0%] among male individuals; 13.1% [95% CI, 10.5%-16.2%] among female individuals), but increased prevalence was associated with age (9.7% [95% CI, 7.4%-12.5%] among adults aged 18-44 years; 13.7% [95% CI, 11.0%-17.0%] among those aged 45-64 years; and 23.6% [95% CI, 19.4%-28.5%] among those aged ≥65 years; P < .001 among age groups). The pooled prevalence of severe tinnitus was 2.3% (95% CI, 1.7%-3.1%), ranging from 0.5% (95% CI, 0.3%-0.7%) to 12.6% (95% CI, 11.1%-14.1%). The pooled prevalence of chronic tinnitus was 9.8% (95% CI, 4.7%-19.3%) and the pooled prevalence of diagnosed tinnitus was 3.4% (95% CI, 2.1%-5.5%). The pooled incidence rate of any tinnitus was 1164 per 100 000 person-years (95% CI, 479-2828 per 100 000 person-years). Conclusions and relevance: Despite the substantial heterogeneity among studies, this comprehensive systematic review on the prevalence and incidence of tinnitus suggests that tinnitus affects more than 740 million adults globally and is perceived as a major problem by more than 120 million people, mostly aged 65 years or older. Health policy makers should consider the global burden of tinnitus, and greater effort should be devoted to boost research on tinnitus.
Article
Objective: Tinnitus has been the No. 1 disability at the Veteran Administration for the last 15 years, yet its interaction with hearing loss secondary to etiologies such as age, noise trauma, and traumatic brain injuries remains poorly characterized. Our objective was to analyze hearing loss and tinnitus, including audiogram data, of the Million Veteran Program within the context of military exposures in an aging population. Design: Health records, questionnaires, audiograms, and military data were aggregated for 758,005 Veteran participants in the Million Veteran Program 2011 to 2020, with relative risks (RR) calculated for ancestries, sex, hearing loss and military exposures such as combat, blast, and military era served. A multivariate model with significant demographic measures and exposures was then analyzed. Next, audiogram data stratified by sex were compared for those with and without tinnitus by two methods: first, mean thresholds at standard frequencies were compared to thresholds adjusted per ISO 7029:2000E age and sex formulae. Second, levels for those ≤40 years of age were compared with those 41 and older. Finally, a proportional hazards model was examined to ascertain the timing between the onset of tinnitus and hearing loss, calculated separately for electronic health record diagnoses (ICD) and self-report. Results: Tinnitus was either self-reported, diagnosed, or both in 37.5% (95% CI, 37.4 to 37.6), mean age 61.5 (95% CI, 61.4 to 61.5), range 18 to 112 years. Those with hearing loss were 4.15 times (95% CI, 4.12 to 4.15) as likely to have tinnitus. Americans of African descent were less likely to manifest tinnitus (RR 0.61, 95% CI, 0.60 to 0.61), as were women (RR 0.65, 95% CI, 0.64 to 0.65). A multivariate model indicated a higher RR of 1.73 for traumatic brain injury (95% CI, 1.71 to 1.73) and daily combat noise exposure (1.17, 95% CI, 1.14 to 1.17) than age (0.998, 95% CI, 0.997 to 0.998). Subjects ≤40 years of age had small but significantly elevated hearing thresholds through all standard frequencies compared to Veterans without tinnitus, and the effect of tinnitus on hearing thresholds diminished with age. In the hazard model, those >40 with new onset of tinnitus were at risk for hearing loss sooner and with greater incidence than those who were younger. The rate of hearing loss following tinnitus approached 100%. In contrast, only approximately 50% of those who self-reported hearing loss initially were at risk for later hearing loss, in contrast to ICD comparison, where those with ICD of hearing loss were more likely to sustain an ICD of tinnitus subsequently. Conclusions: Evidence suggests that the occurrence of tinnitus in the military is more closely related to environmental exposures than to aging. The finding that tinnitus affects hearing frequencies across the audiogram spectrum suggests an acoustic injury independent of tonotopicity. Particularly for males >40, tinnitus may be a harbinger of audiologic damage predictive of later hearing loss.
Article
Objective: Summarize and analyze the current research results of tinnitus-related genes, explore the potential links between the results of each study, and provide reference for subsequent studies. Methods: Collect and sort out the research literature related to tinnitus genes included in PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform before December 31, 2019. Then the relevant contents of the literature were sorted out and summarized. Results: Fifty-one articles were finally selected for analysis: 31 articles (60.8%) were classified as researches on animal models of tinnitus, and 20 (39.2%) as researches on tinnitus patients. Existing studies have shown that genes related to oxidative stress, inflammatory response, nerve excitation/inhibition, and nerve growth are differentially expressed in tinnitus patients or animal models, and have presented the potential links between genes or proteins in the occurrence and development of tinnitus. Conclusion: The research on tinnitus-related genes is still in the exploratory stage, and further high-quality research evidence is needed.
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Genome-wide association studies (GWAS) provide an unbiased first look at genetic loci involved in aging and noise-induced sensorineural hearing loss and tinnitus. The hearing phenotype, whether audiogram-based or self-report, is regressed against genotyped information at representative single nucleotide polymorphisms (SNPs) across the genome. Findings include the fact that both hearing loss and tinnitus are polygenic disorders, with up to thousands of genes, each of effect size of < 0.02. Smaller human GWAS’ were able to use objective measures and identified a few loci; however, hundreds of thousands of participants have been required for the statistical power to identify significant variants, and GWAS is unable to assess rare variants with mean allele frequency < 1%. Animal studies are required as well because of inability to access the human cochlea. Mouse GWAS builds on linkage techniques and the known phenotypic differences in auditory function between inbred strains. With the advantage that the laboratory environment can be controlled for noise and aging, the Hybrid Mouse Diversity Panel (HDMP) combines 100 strains sequenced at high resolution. Lift-over regions between mice and humans have identified over 17,000 homologous genes. Since most significant SNPs are either intergenic or in introns, and binding sites between species are poorly preserved between species, expression quantitative trait locus information is required to bring humans and mice into agreement. Transcriptome-wide analysis studies (TWAS) can prioritize putative causal genes and tissues. Diverse species, each making a distinct contribution, carry a synergistic advantage in the quest for treatment and ultimate cure of sensorineural hearing difficulties.
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Background: Tinnitus service provision in the United Kingdom has been investigated from the healthcare provider's perspective demonstrating considerable regional variation particularly regarding availability of psychological treatments. An audiological-based tinnitus service, however, was reportedly available for all tinnitus patients in the UK. The aim of the current study was to define and evaluate nationwide tinnitus healthcare services from the patients' viewpoint. Methods: Secondary analyses were performed on data from a 33-item questionnaire provided by the British Tinnitus Association. The questionnaire had been distributed via email and social media. Results: Responses from 937 participants who had or had previously experienced tinnitus were analysed. All but one person had at some time consulted their GP. About one in five received medication in primary care. The majority were referred to secondary care, generally an ENT surgeon or audiovestibular physician; some were referred directly to audiological services. In secondary care the majority underwent audiometric testing and over half underwent MRI scanning. Drugs were prescribed less frequently in secondary care. About one third of patients were referred onwards from diagnostic services in secondary care to receive therapeutic interventions for tinnitus. Therapy was generally delivered by an audiologist or hearing therapist. Just under two fifths of people discharged from secondary care returned to their GP, with most returning within one year. Over a third of this group were re-referred to secondary care. Few patients saw a psychologist (2.6%) though some psychological treatments were delivered by appropriately trained audiologists. Negative counselling from healthcare professionals in both primary and secondary care settings was reported. Conclusions: Although the UK has developed a national service for patients with tinnitus many people find it difficult to access, being blocked at the primary care level or after secondary care diagnostic services. Many of those discharged from secondary care return to their GP within a short space of time and are re-referred to secondary care creating an unsatisfactory and expensive revolving-door pattern of healthcare. Despite psychological treatment modalities having the best evidence base for successful tinnitus management, only a minority of tinnitus patients ever get to meet a psychologist.
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The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve inputs from the cochlea with somatosensory inputs from the head and neck. In previous work, we developed a guinea pig model of tinnitus induced by noise exposure and showed that the fusiform cells in these animals exhibited increased spontaneous activity and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold promise for suppressing chronic tinnitus, which reduces quality of life for millions of tinnitus sufferers worldwide.
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Objectives Irritable bowel syndrome (IBS) clusters in families, but the familial risk of IBS has not been determined in adoptees. Studying adoptees and their biological and adoptive parents is a strong study design for separating genetic from environmental causes of familial clustering. This nationwide study aimed to separate the biological (genetic) and familial environmental contribution to the familial transmission of IBS. Methods We performed a family study for Swedish-born adoptees born from 1951 until 1995, and their biological and adoptive parents. The Swedish Multigeneration Register was linked to the Hospital Register (inpatients and outpatients) for the period 1964–2012 and the Swedish Outpatient Care Register for 2001–2012, and the Swedish Primary Healthcare register for 1989–2012. ORs for IBS were calculated for adoptees with an affected biological parent with IBS compared with adoptees without a biological parent with IBS. The OR for IBS was also determined in adoptees with an adoptive parent with IBS compared with adoptees without an adoptive parent with IBS. Heritability h ² (±SE) was also determined. Results The ORs for IBS were 1.67 in adoptees (95% CI 1.06 to 2.62) of biological parents diagnosed with IBS. The ORs for IBS were 0.88 in adoptees (95% CI 0.48 to 1.63) of adoptive parents diagnosed with IBS. The heritability was 19.5%±8.5%. Conclusions The present study indicates that biological (genetic) factors are important for the familial clustering of IBS. The heritability calculated is in the range from twin studies and suggests that heritability may be estimated in adoptees.
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Many studies have explored how neuromodulators affect synaptic function, yet little is known about how they modify computations at the microcircuit level. In the dorsal cochlear nucleus (DCN), a region that integrates auditory and multisensory inputs from two distinct pathways, serotonin (5-HT) enhances excitability of principal cells, predicting a generalized reduction in sensory thresholds. Surprisingly, we found that when looked at from the circuit level, 5-HT enhances signaling only from the multisensory input, while decreasing input from auditory fibers. This effect is only partially explained by an action on auditory nerve terminals. Rather, 5-HT biases processing for one input pathway by simultaneously enhancing excitability in the principal cell and in a pathway-specific feed-forward inhibitory interneuron. Thus, by acting on multiple targets, 5-HT orchestrates a fundamental shift in representation of convergent auditory and multisensory pathways, enhancing the potency of non-auditory signals in a classical auditory pathway.
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Background The assessment and treatment of complex disorders is challenged by the multiple domains and instruments used to evaluate clinical outcome. With the large number of assessment tools typically used in complex disorders comes the challenge of obtaining an integrative view of disease status to further evaluate treatment outcome both at the individual level and at the group level. Radar plots appear as an attractive visual tool to display multivariate data on a two-dimensional graphical illustration. Here, we describe the use of radar plots for the visualization of disease characteristics applied in the context of tinnitus, a complex and heterogeneous condition, the treatment of which has shown mixed success. Methods Data from two different cohorts, the Swedish Tinnitus Outreach Project (STOP) and the Tinnitus Research Initiative (TRI) database, were used. STOP is a population-based cohort where cross-sectional data from 1,223 non-tinnitus and 933 tinnitus subjects were analyzed. By contrast, the TRI contained data from 571 patients who underwent various treatments and whose Clinical Global Impression (CGI) score was accessible to infer treatment outcome. In the latter, 34,560 permutations were tested to evaluate whether a particular ordering of the instruments could reflect better the treatment outcome measured with the CGI. Results Radar plots confirmed that tinnitus subtypes such as occasional and chronic tinnitus from the STOP cohort could be strikingly different, and helped appreciate a gender bias in tinnitus severity. Radar plots with greater surface areas were consistent with greater burden, and enabled a rapid appreciation of the global distress associated with tinnitus in patients categorized according to tinnitus severity. Permutations in the arrangement of instruments allowed to identify a configuration with minimal variance and maximized surface difference between CGI groups from the TRI database, thus affording a means of optimally evaluating the outcomes in individual patients. Conclusion We anticipate such a tool to become a starting point for more sophisticated measures in clinical outcomes, applicable not only in the context of tinnitus but also in other complex diseases where the integration of multiple variables is needed for a comprehensive evaluation of treatment response.
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Tinnitus is the perception of a phantom sound that affects between 10 and 15% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.
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Purpose: Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). Methods: Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. Results: Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. Conclusion: Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017Genetics in Medicine (2017); doi:10.1038/gim.2017.4.
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Tinnitus, the perception of an auditory phantom sound in the form of ringing, buzzing, roaring, or hissing in the absence of an external sound source, is perceived by ~15% of the population and 2.5% experiences a severely bothersome tinnitus. The contribution of genes on the development of tinnitus is still under debate. The current manuscript reports a pilot Genome Wide Association Study (GWAS) into tinnitus, in a small cohort of 167 independent tinnitus subjects, and 749 non-tinnitus controls, who were collected as part of a cross-sectional study. After genotyping, imputation, and quality checking, the association between the tinnitus phenotype and 4,000,000 single-nucleotide polymorphisms (SNPs) was tested followed by gene set enrichment analysis. None of the SNPs reached the threshold for genome-wide significance (p < 5.0e–8), with the most significant SNPs, situated outside coding genes, reaching a p-value of 3.4e–7. By using the Genetic Analysis of Complex Traits (GACT) software, the percentage of the variance explained by all SNPs in the GWAS was estimated to be 3.2%, indicating that additive genetic effects explain only a small fraction of the tinnitus phenotype. Despite the lack of genome-wide significant SNPs, which is, at least in part, due to the limited sample size of the current study, evidence was found for a genetic involvement in tinnitus. Gene set enrichment analysis showed several metabolic pathways to be significantly enriched with SNPs having a low p-value in the GWAS. These pathways are involved in oxidative stress, endoplasmatic reticulum (ER) stress, and serotonin reception mediated signaling. These results are a promising basis for further research into the genetic basis of tinnitus, including GWAS with larger sample sizes and considering tinnitus subtypes for which a greater genetic contribution is more likely.
Article
Background: Though clinical guidelines for assessment and treatment of chronic subjective tinnitus do exist, a comprehensive review of those guidelines has not been performed. The objective of this review was to identify current clinical guidelines, and compare their recommendations for the assessment and treatment of subjective tinnitus in adults. Method: We systematically searched a range of sources for clinical guidelines (as defined by the Institute of Medicine, United States) for the assessment and/or treatment of subjective tinnitus in adults. No restrictions on language or year of publication were applied to guidelines. Results: Clinical guidelines from Denmark, Germany, Sweden, The Netherlands, and the United States were included in the review. There was a high level of consistency across the guidelines with regard to recommendations for audiometric assessment, physical examination, use of a validated questionnaire(s) to assess tinnitus related distress, and referral to a psychologist when required. Cognitive behavioral treatment for tinnitus related distress, use of hearing aids in instances of hearing loss and recommendations against the use of medicines were consistent across the included guidelines. Differences between the guidelines centered on the use of imaging in assessment procedures and sound therapy as a form of treatment for tinnitus distress respectively. Conclusion: Given the level of commonality across tinnitus guidelines from different countries the development of a European guideline for the assessment and treatment of subjective tinnitus in adults seems feasible. This guideline would have the potential to benefit the large number of clinicians in countries where clinical guidelines do not yet exist, and would support standardization of treatment for patients across Europe.