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Autism spectrum disorder diagnosis in adults: phenotype and genotype findings from a clinically derived cohort



Background The past decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared with children, little is known about the phenotypic and genetic characteristics of these patients. Aims This e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically presenting sample of adults diagnosed with ASD by specialist services. Method Individuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA; 105 eligible individuals were matched to 76 healthy controls. We investigated demographics, social history and comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores were calculated. Results Of individuals with ASD, 89.5% had at least one comorbid psychiatric diagnosis, with depression (62.9%) and anxiety (55.2%) being the most common. The ASD group experienced more neurological comorbidities than controls, particularly migraine headache. They were less likely to have married or be in work, and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared with controls, but there was no difference in the rate of rare CNVs. Conclusions This study provides important information about psychiatric comorbidity in adult ASD, which may inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within the non-intellectually disabled population of adults with ASD. Declaration of interest None.
Autism spectrum disorder diagnosis in adults:
phenotype and genotype findings from a clinically
derived cohort
Jack F. G. Underwood, Kimberley M. Kendall, Jennifer Berrett, Catrin Lewis, Richard Anney,
Marianne B. M. van den Bree and Jeremy Hall
The past decade has seen the development of services for adults
presenting with symptoms of autism spectrum disorder (ASD) in
the UK. Compared with children, little is known about the
phenotypic and genetic characteristics of these patients.
This e-cohort study aimed to examine the phenotypic and gen-
etic characteristics of a clinically presenting sample of adults
diagnosed with ASD by specialist services.
Individuals diagnosed with ASD as adults were recruited by the
National Centre for Mental Health and completed self-report
questionnaires, interviews and provided DNA; 105 eligible indi-
viduals were matched to 76 healthy controls. We investigated
demographics, social history and comorbid psychiatric and
physical disorders. Samples were genotyped, copy number
variants (CNVs) were called and polygenic risk scores were
Of individuals with ASD, 89.5% had at least one comorbid psy-
chiatric diagnosis, with depression (62.9%) and anxiety (55.2%)
being the most common. The ASD group experienced more
neurological comorbidities than controls, particularly migraine
headache. They were less likely to have married or be in work,
and had more alcohol-related problems. There was a signifi-
cantly higher load of autism common genetic variants in the
adult ASD group compared with controls, but there was no dif-
ference in the rate of rare CNVs.
This study provides important information about psychiatric
comorbidity in adult ASD, which may inform clinical practice and
patient counselling. It also suggests that the polygenic load of
common ASD-associated variants may be important in confer-
ring risk within the non-intellectually disabled population of
adults with ASD.
Declaration of interest
Autistic spectrum disorders; genetics; social functioning.
Copyright and usage
© The Royal College of Psychiatrists 2019. This is an Open Access
article, distributed under the terms of the Creative Commons
Attribution licence (
4.0/), which permits unrestricted re-use, distribution, and
reproduction in any medium, provided the original work is
properly cited.
Autism spectrum disorder (ASD) is a group of neurodevelopmental
disorders characterised by persistent difficulties in social interaction
and communication, as well as restricted interests, stereotypic beha-
viours and resistance to change.
Epidemiological studies report a
prevalence of ASD in the general population of around 1%, with a
male:female ratio of approximately 3:1.
The majority of studies
of ASD have been carried out in paediatric populations and have
included individuals with intellectual disability. The limited studies
in individuals diagnosed with ASD as adults have shown that
adults with ASD experience significant disadvantage in employment,
social relationships and quality of life.
ASD has also been
associated with increased lifetime psychiatric comorbidity.
Research has particularly focussed on anxiety and depression,
where a meta-analysis by Hollocks et al demonstrated lifetime rate
estimates of 42% and 37%, respectively.
This analysis found con-
siderable heterogeneity between the studies, and no studies examin-
ing comorbidity in non-clinical samples of adults with ASD.
has been very little research reporting lifetime outcomes for indivi-
duals diagnosed with ASD as adults. This information has the poten-
tial to inform specialist service development and tailor clinical care.
Advancing knowledge in this area is important because since the
Autism Act 2009 and recommendations in the National Institute
for Health and Care Excellence Guidelines of 2012, many adult
ASD diagnostic services have been set up across the UK, although
provision remains sporadic.
Furthermore, although some adult
services now offer genetic testing for individuals diagnosed with
ASD, little is known about the genetic characteristics of adults pre-
senting with ASD. Studies of predominantly paediatric ASD popula-
tions have shown a substantial contribution of both rare copy
number variants (CNVs) and polygenic burden of common variants
to risk for ASD. Rare CNVs are reported to occur in 1015% of child-
hood ASD cases, which has encouraged formal genetic testing in
childhood ASD.
However, it is not known whether similar
rates are seen in individuals presenting to adult diagnostic services.
In this study we examine the demographic, social, psychiatric and
physical health characteristics of a cohort of individuals presenting
with ASD in adulthood compared with a healthy control population
from the same source databank. We also report the rates of neurode-
velopmental CNVs and polygenic burden of common variants asso-
ciated with ASD in this sample.
Data was obtained from the National Centre for Mental Health
(NCMH,, a Welsh Government-funded
Research Centre that investigates neurodevelopmental, adult
and neurodegenerative psychiatric disorders across the lifespan.
Participants were recruited using a variety of systematic approaches
in primary, secondary and tertiary healthcare services, including the
identification of potential participants by clinical care teams,
The British Journal of Psychiatry (2019)
Page 1 of 7. doi: 10.1192/bjp.2019.30
screening of clinical notes and the use of disease registers. The
majority of participants in our sample were recruited via specialist
diagnostic services. Non-systematic recruitment approaches
included advertising in local media, placing posters and leaflets in
National Health Service waiting areas, liaising with voluntary orga-
nisations and contacting individuals enrolled in previous studies
within the Institute of Psychological Medicine and Clinical
Neurosciences, Cardiff, UK. To allow comparisons, the cohort
includes control participants who self-report no experiences of
any mental health disorder. All adult participants included in this
study provided written informed consent for recruitment into the
NCMH. Trained research assistants administered a brief standar-
dised interview assessment to consenting participants to ascertain
details related to the participants personal and family history of
mental health experiences, including any comorbidity, past and
current medication use, sociodemographic information including
employment and education, physical health diagnoses and any sub-
stance misuse. A sample of venous blood or saliva was taken for
genetic and other analyses. Participants were given a pack of stan-
dardised self-report questionnaires to complete and return to the
research team by post after the initial assessment. Confirmation
and further information regarding the primary diagnosis of ASD
was obtained from clinical records where appropriate consent had
been obtained to do so.
To date, 10 870 individuals have been recruited to the NCMH. At
the point of initial search in June 2016, the database included approxi-
mately 6600 participants, of whom 172 held a primary self-report
diagnosis of Asperger syndrome, ASD or autism and no self-report
comorbid intellectual disability, and were potentially eligible for
inclusion. On case-note review, 67 out of 172 participants were
excluded, predominantly because of loss of contact with the
NCMH to confirm diagnosis (n= 37; full details in Supplementary
Material, available at The
remaining 105 individuals were all confirmed to have an ASD diag-
nosis consistent with ICD-10criteria by case-note review, with no evi-
dence of recorded intellectual disability and with a first diagnosis of
ASD made by secondary care clinicians assessing in a diagnostic
role when the participant was over 18 years of age.
Seventy-six con-
trols were randomly selected from a derived cohortmatched pairwise
on age (within 5 years and over 18 years), ethnicity and gender from
the NCMH database. Control participants were selected from indivi-
duals in the NCMH database with no current or previous self-
reported difficulties with mental health and no psychotropic medica-
tion usage. A favourable ethical opinion was received from the Wales
Research Ethics Committee 2 on 25 November 2016 for the NCMH,
and through internal NCMH applications for this study.
Demographic information
Demographic data was collected by interview and questionnaire.
Biological offspring was recorded as a binary yes/no variable and
with free-text number and biological age of children, recorded in
101 of the 105 participants with ASD and all controls. Lifetime
marriage and cohabitation was recorded as a binary yes/no variable,
recorded in 97 ofthe participants and all 76 controls. Current profes-
sion responses were multiple-choice skill level (see Supplementary
Material for categorisation), reduced to currently in work/currently
not in workfor our analysis and recorded for 97 participants with
ASD and 73 controls.
Physical health comorbidities were established with a multiple-
choice list of 22 common physical diagnoses selected for collection
at the inception of the NCMH (Supplementary Material), reduced
to clinical system categories for comparison. Lifetime mental
health comorbidities were established with a multiple-choice
list of 37 common psychiatric diagnoses, as reported in the
Supplementary Material. By definition the control group had no
psychiatric comorbidity for comparative analysis, thus preventing
comparative analysis of mental health comorbid rates. Fifty-nine
participants with ASD and 53 control participants completed the
Beck Depression Inventory (BDI),
providing information on
current mood. Information on lifetime psychotropic medication
usage was collected by medication class and provided by between
93 and 95 participants with ASD, dependent upon the question
response rate.
Substance use
Individuals reported on problems encountered in their lifetime
through substance use in financial, medical, relationship and occu-
pational domains. For analysis purposes these were reduced to
binary yes/no categories. Fifty-eight participants with ASD and 60
out of 76 control participants responded to alcohol problem ques-
tions. Regular smoking was reported as a binary yes/no variable,
as was regular cannabinoid use, with complete data available for
79 participants with ASD and all controls. Regular cannabinoid
use was reported as a binary yes/no variable and completed by 31
participants with ASD and 25 control participants. Usage of other
street drugs was recorded as an initial binary yes/no variable and,
if positive, through a multiple-choice question incorporating
common UK street drugs. Eighty participants with ASD and all con-
trols responded to the initial question, with 13 participants with
ASD and 13 controls giving further answers.
Phenotype statistical analysis
Statistical analysis was performed with IBM SPSS Statistics version
23 for Windows.
Prevalence of comorbid psychiatric disorders
was analysed through descriptive statistics for mean, s.d., variance
and range. No comparative statistics of comorbid psychiatric diag-
nosis and associated medication usage was possible as by definition
our control population was unaffected. Prevalence of sociodemo-
graphic, physical health comorbidity and family history was initially
graphed. For normally distributed dependent variables, analysis was
performed by χ²-test followed by a binomial logistic regression with
ASD diagnosis (yes/no), with age and gender entered as covariates.
Where dependent variables were non-normal, a non-parametric
MannWhitney U-test was used, with Fishers exact test for
expected cell counts fewer than five.
DNA was obtained from blood and saliva samples, and genotyping
was carried out at the Medical Research Council Centre for
Neuropsychiatric Genetics and Genomics (Hadyn Ellis
Laboratory, Cardiff University, Wales). Samples were available
from 90 individuals with ASD and 60 control participants.
Individuals were genotyped on two versions of the Illumina
Infinium PsychArray: the Infinium PsychArray 24v1-2 (34 indivi-
duals with ASD, 59 controls) and the Infinium PsychArray with
custom content (IPMCN PsychChip; 56 individuals with ASD,
1 control).
CNV calling
CNVs were called using PennCNV run through a custom Galaxy
Individual samples were excluded if they had 30
CNVs, a waviness factor >0.03 or <0.03 or a call rate <96%.
Individual CNVs were excluded if their log R ratio (LRR) s.d. was
Underwood et al
>0.2. CNVs constituting <50 kb or >10 single nucleotide polymorph-
isms (SNPs) were removed, using a UNIX-based script before anno-
tation (Supplementary Material); 373 samples remained after quality
control. We annotated the CNVs called with a list of 53 CNVs
associated with neurodevelopmental disorders (Supplementary
The breakpoints of the initial call of CNVs were
inspected to confirm they met the CNV calling criteria. We required
a CNV to cover more than half the critical interval and to include key
genes in the region (if known), or in the case ofsingle-gene CNVs, we
required deletions to intersect at least one exon and duplications to
cover the whole gene.
Polygenic risk scores
Genotype quality control was performed separately for polygenic
risk scores (PRS), using the self-authored function genotypeqc in
Stata. Full genotype quality control, genome-wide association
study (GWAS) quality control and GWAS and genotype merging
methods can be found in the Supplementary Material. After
quality control, PRS were calculated on a subset of linkage inde-
pendent markers (r
< 0.2) generated using the clump flag in
PLINK. All risk scores were calculated based on the riskallele,
with weights for each risk allele taken from the GWAS beta-
coefficient (calculated as the natural log of the GWAS odds ratio).
PRS were calculated for ASD,
attention-deficit hyperactivity dis-
order (ADHD),
major depressive disorder
and schizophrenia,
using the score flag in PLINK. Missing genotypes were scored
using the mean imputation routine. PRS were calculated for the
linkage independent markers with associations at ten P-value
thresholds (P< 0.5, <0.1, <0.05, <10
, <10
, <10
, <10
, <10
and <10
). SNPs included in each model are available
on request.
By definition, control participants did not have psychiatric morbid-
ity and were not using any psychotropic medication.
Psychiatric comorbidity
Comorbid psychiatric diagnosis was reported by 89.5% (n= 94) of
individuals with ASD (Table 1). The most common comorbid diag-
noses were depression (62.9%, n= 66) and anxiety (55.2%, n= 58);
44.8% of individuals with ASD reported dual depression and anxiety
diagnoses. The mean BDI score for the participants with ASD was
20.356, which is on the border of mild (1419) and moderate
(2028) depression severity. The mean for the control participants
was 5.226, significantly different from the participants with ASD
(U= 328.5, Z-score of 7.205, r=0.68, P<0.001), and within the
minimal range (013). The significant association was seen across
all BDI subscale scores except for question 19 (weight change).
Psychotropic medication usage
The most widely prescribed medications among participants with
ASD were antidepressants and anxiolytics, and over a quarter
reported taking antipsychotics (Table 2).
Sociodemographic phenotype
Data comparing sociodemographic phenotypes, physical health and
family history for participants with ASD and controls are presented
in Table 3. The average age of the participants with ASD was 37.8
years (s.d. 12.3) and for controls it was 40.7 years (s.d. 14.1, P=
0.89) because of matching. There were 80 males and 25 females
among the participants with ASD (76.2% male), and 55 males and
21 females in the control participants (72.4% male, P= 0.56).
Adults with ASD were significantly less likely to be currently
working (odds ratio 0.174, P<0.001), to be married or cohabiting
(odds ratio 0.29, P= 0.002), to be currently off work because of sick-
ness or disablement (odds ratio 69.305, P<0.001) and to have
Table 1 Psychiatric comorbidity as defined by ICD-10
ICD-10 code
Participants with
ASD (n= 105)
All comorbid
94 (89.5%)
Mood (affective) disorder
Any 69 (65.7%)
Depression 66 (62.9%)
Bipolar disorder 9 (8.6%)
Hypomania <3 (<2.9%)
Neurotic, stress-related
and somatoform
Any 63 (60.0%)
Anxiety 58 (55.2%)
OCD 18 (17.1%)
Phobias 9 (8.6%)
Agoraphobia 8 (7.6%)
Panic disorder 8 (7.6%)
PTSD 6 (5.7%)
Any 30 (28.6%)
Dyslexia 23 (21.9%)
Dyspraxia 19 (18.1%)
Disorders with onset
occurring in childhood or
Any 22 (21.0%)
ADHD 20 (19.0%)
Oppositional defiant
<3 (<2.9%)
Tic disorders <3 (<2.9%)
schizotypal and
delusional disorders
Any 13 (12.4%)
Psychosis 12 (11.4%)
Schizophrenia 4 (3.8%)
3 (2.9%)
Disorders due to
substance use
Any 13 (12.4%)
Alcohol misuse 10 (9.5%)
Other substance
9 (8.6%)
Syndromes associated
with physiological
Any 8 (7.6%)
Anorexia 4 (3.8%)
Postnatal depression 3 (2.9%)
Bulimia <3 (<2.9%)
Disorders of adult
Any 4 (3.8%)
Borderline personality
3 (2.9%)
Other personality
<3 (<2.9%)
Organic disorders
Picks disease
<3 (<2.9%)
Reported psychiatric comorbidity in participants with ASD grouped by ICD-10 classifi-
cation. nindicates the number of individuals reporting the diagnosis; % indicates the
percentage of the total amount of participants that responded.
ASD, autism spectrum disorder; OCD, obsessivecompulsive disorder; PTSD, post-
traumatic stress disorder; ADHD, attention-deficit hyperactivity disorder.
Table 2 Psychotropic medication usage among participants with ASD
Reported lifetime use, n(%)
Stimulants 6 (6.3%)
Antidepressants 74 (78.7%)
Anxiolytics 29 (31.2%)
Hypnotics 17 (18.1%)
Mood stabilisers 6 (6.5%)
Antipsychotics 25 (26.3%)
Reported psychotropic medication usage in participants with ASD based on the National
Centre for Mental Health questionnaire response fields. nindicates the number of
individuals reporting usage of medication of this type; % indicates the percentage of the
total amount of participants that responded.
ASD, autism spectrum disorder.
ASD diagnosis in adults
alcohol-related problem (odds ratio 6.24, P= 0.001). No differences
were found in rates of having one or more biological children.
Physical health comorbidity
Adults with ASD were more likely to have neurological problems
than controls (odds ratio 2.83, P= 0.004). Post hoc analysis within
the neurological subgroup explored whether differences in the
rates between participants with ASD and controls could be
explained by comorbid epilepsy and seizure disorder, conditions
reported to co-occur at elevated rates paediatric ASD populations.
This demonstrated that the effect was predominantly because of
an increased reported rate of migraine in individuals with ASD.
Forty-one (42.7%) individuals with ASD reported lifetime history
of migraine headaches compared with 15 (20.5%) control partici-
pants (odds ratio 2.60, P= 0.012, 95% CI 1.245.44). Eight indivi-
duals with ASD reported a lifetime history of epilepsy and seizure
disorder compared with three control participants (odds ratio
2.15, P= 0.273, 95% CI 0.558.49). A further association between
migraine headaches and epilepsy and seizure disorders was con-
firmed (odds ratio 11.38, P= 0.028).
Family history of psychiatric disorder
Reported family history of autism was seen at a greater rate among
participants with ASD (OR = 2.16, P= 0.041), but no differences
were found for family history of ADHD, bipolar disorder, schizo-
phrenia, dementia or post-traumatic stress disorder.
Genetic analysis
CNV analysis
The 53 neurodevelopmental CNVs tested for were present in 3.8%
(n= 4) of participants with ASD and 1.3% (n= 1) of controls. The
CNVs in participants with ASD were 2q13 deletion (n= 2),
15q13.3 duplication (n= 1) and 16p13.11 duplication (n= 1).
A single 2p16.3 deletion was found in one control.
Analyses of PRS
PRS derived from GWAS of ASD, ADHD, major depressive dis-
order and schizophrenia were calculated for each individual. Only
the PRS derived from the ASD GWAS showed differences
between cases and controls (Fig. 1); despite the modest sample
size of this cohort, we calculate that approximately 12.86% (P<
0.00001) of variance can be explained from PRS derived from
linkage independent markers showing association at P< 0.001 in
the ASD GWAS (433 SNPs in model). No significant difference
between cases and controls was seen for PRS for ADHD, major
depressive disorder or schizophrenia.
In this study we report on the phenotypic characteristics and genetic
profiles of a sample of individuals with ASD diagnosed in adulthood
without intellectual disability. We found high rates of psychiatric
comorbidity, problem alcohol use and medication usage in individuals
with ASD. These individuals also had higher rates of neurological
comorbidity than controls and there was an association between ASD
diagnosis and migraine. There was a significant association between
PRS for ASD and a diagnosis of ASD, but no significant increase in
rate of rare neurodevelopmental CNVs in individuals with ASD.
A total of 89.5% of participants with ASD reported a further lifetime
psychiatric comorbidity, comparable with previously reported popula-
tions including those diagnosed as adults or with intellectual disability
Depression was the most common lifetime comorbid
diagnosis with a rate of 62.9%, comparable with previously reported
rates (5370%) in larger samples including those diagnosed as chil-
dren or with intellectual disability.
Lifetime anxiety diagnosis
rates of around 50% were also similar to previously reported in
those with ASD but with intellectual disability.
The implication
Table 3 Physical health comorbidity, family history, social demographics and substance use in participants with ASD and matched controls
Participants with ASD (n, %) Matched controls (n, %) Odds ratio (95% CI) Pvalue
Currently working 31, 32.0% 53, 72.6% 0.174 (0.090.35) <0.001
Currently not working because of sickness/disablement 48, 49.5% 1, 0.01% 69.305 (9.23520.42) <0.001
Biological children 36, 35.6% 41, 54.0% 0.526 (0.261.05) 0.068
Married or cohabiting 49, 50.5% 58, 76.3% 0.29 (0.140.64) 0.002
Regular smoker 34, 43.0% 35, 46.1% 1.017 (0.991.04) 0.169
Problems due to alcohol use 21, 36.2% 5, 8.3% 6.42 (2.2018.72) 0.001
Regular cannabinoids use 22, 27.9% 16, 21.1% 1.00 (0.971.03) 0.903
Problems due to cannabinoid use 9, 29.0% 4, 16.0% 1.02 (0.961.08) 0.590
Use of other street drugs 10, 12.5% 4, 5.3% 0.99 (0.951.04) 0.711
Problems due to other street drugs use 4, 33.3% 1, 7.7% 0.98 (0.891.08) 0.682
Physical health comorbidity
Respiratory 36, 34.3% 16, 21.1% 1.84 (0.913.71) 0.089
Neurological 42, 40.0% 14, 14.0% 2.83 (1.405.74) 0.004
Metabolic 18, 17.1% 8, 18.4% 1.66 (0.674.11) 0.269
Rheumatological and orthopaedic 12, 11.4% 3, 3.9% 3.06 (0.8211.33) 0.095
Cardiological 17, 16.2% 6, 7.9% 2.09 (0.775.66) 0.148
Renal and gastrointestinal 5, 4.8% 4, 5.3% 0.91 (0.233.59) 0.896
Oncological 1, 1.0% 0, 0% 0.996
Family history
FHx ADHD 14 (14.1%) 9 (12.2%) 1.22 (0.493.02) 0.674
FHx bipolar disorder 9 (9.3%) 11 (15.1%) 0.58 (0.221.51) 0.265
FHx schizophrenia 6 (6.3%) 3 (4.1%) 1.58 (0.386.60) 0.529
FHx dementia 22 (22.4%) 16 (22.5%) 1.01 (0.482.11) 0.977
FHx PTSD 5 (5.1%) 2 (2.7%) 1.80 (0.349.67) 0.491
FHx autism 30 (34.1%) 16 (21.6%) 2.16 (1.034.53) 0.041
Reported physical health comorbidity, family health history, social demographics and substance use in participants with ASD based on the National Centre for Mental Health questionnaire
response fields. The comparison group are matched healthy controls. For normally distributed samples, analyses were binomial logistic regression, with age and gender as covariates.
Where data were non-normally distributed, the non-parametric MannWhitney U-test was used, with Fishers exact test for expected cell counts fewer than five. nindicates the number of
individuals; % indicates the percentage of the total amount of participants that responded.
ASD, autism spectrum disorder; FHx, reported family history; ADHD, attention-deficit hyperactivity disorder; PTSD, post-traumatic stress disorder.
Underwood et al
that a primary diagnosis of ASD is linked to high lifetime rates of
anxiety and depression even in populations without intellectual dis-
ability is important for clinical consultations. Whether the aetiology
of ASD predisposes for depression and anxiety, or life events and dif-
ficulties experienced by individuals because of their ASD precipitate
depression and anxiety, or both, is a chicken and eggconundrum
worthy of further study.
Rates of dyslexia (21.9%), dyspraxia (18.1%) and ADHD
(19.0%), although elevated compared to the general population,
were lower than in previous studies of ASD, which have mainly
been in children.
As our population were diagnosed as adults,
fewer of the neurodevelopmental features that prompt assessment
may be expected, and such a profile fits with genetic findings.
Shared aetiology may explain the significantly higher rates of neuro-
logical conditions seen in participants with ASD, predominantly
due to a strong prevalence of comorbid migraine. Although a patho-
physiological link has been suggested for this in the past, this is the
first clear evidence of an association, to our knowledge, and
warrants further investigation.
Lifetime psychotropic medication usage was concordant with
the diagnosis findings. Nearly 80% of the population had taken anti-
depressant medications during their lifetime, greater than the rates
predicted in the literature.
Further, 26.3% reported taking anti-
psychotic medication when only 12.4% had a diagnosis of psychosis.
This may be partly due to antipsychotic medication usage among
four of the nine individuals reporting bipolar disorder, or for off-
label use for symptomatic or behavioural management as is evi-
denced in adolescents and young adults.
Social demographics
The approximate 3:1 male:female ratio seen in our population
was consistent with reported gender differences.
alcohol and other substance use and smoking rates in our control
and participants with ASD were broadly similar, ASD was asso-
ciated with higher rates of problematic alcohol use. The reasons
were unclear, but could be usage to self-medicate for the aforemen-
tioned anxiety as suggested by other authors, or to facilitate social
Adults with ASD were found to be more than five times less
likely to be employed individuals, with most reporting they were
unemployed or unable to work because of illness. This suggests
supportive employment is available for too few.
We hypothesise
that difficulties with social communication underlie the strikingly
lower rate of marriage for those with ASD; however, interestingly,
the difference in rates of biological children was not significant.
This points to the clear impact of ASD even when diagnosed in
adulthood, and the contribution of comorbid psychiatric conditions
to the life experience of an individual with ASD.
Genetic risk
Previous studies have demonstrated the strong heritability of ASD.
As expected, we demonstrated that adults with ASD were significantly
more likely to have family members with ASD. There were no other
significant associations with mental health disorder family history.
This result may be of use for patients presenting to clinical practice
wanting to know associated family risks, but requires confirmation
from a larger study. Participants with ASD had a slightly higher
number of neurodevelopmental disorderassociated CNVs than con-
trols, although this was not statistically significant in this sample.
Although a statistically significant increase in burden of CNVs in
this group might be confirmed in a larger population, rates were mark-
edly lower than those reported in paediatric ASD populations, who
may have a greater overall neurodevelopmental symptom profile.
PRS analysis demonstrated a significant contribution of polygenic
load of ASD-associated common variants to risk in adult participants
with ASD.
It is noticeable that a significantly increased poly-
genic risk burden was detected even in this relatively small sample
size. Taken together, these results suggest that adults presenting
with ASD may have a lower burden of rare penetrant variants and a
higher polygenic contribution of common risk alleles than childhood
ASD populations, potentially reflecting less severe neurodevelopmen-
tal disability.
The sample used in this study was drawn from the NCMH database,
a resource rich in phenotypic data, and participants consented for
anonymised genetic analysis. NCMH recruits through multiple
methodologies. Sixty-nine of our 105 individuals with ASD were
recruited from secondary ASD diagnostic services, a help-seeking
population, and therefore our results may overestimate comorbidity
rates reflective of recruitment bias. The benefit of the extensive
range of data is offset by clinical diagnoses being initially self-
reported, necessitating a review of the individualsnotes to
confirm specific diagnoses by specialist clinicians. All ASD diagno-
ses in this study were confirmed against ICD-10 diagnostic criteria.
This prevents analysis by symptom severity and lacks the clarity of
diagnostic scoring systems or rating scales such as the Autism
Diagnostic Interview Revised (ADI-R) however, this reflects the
Variance explaines by PRS
not significant P<0.05 P<0.01 P<0.001 P<0.0001
0.00001 0.0001 0.001 0.01 0.05 0.1 0.5
Fig. 1 Percentage variance explained by PRS at analysed association levels for ASD. Percentage variance at eight association marker levels
derived from linkage independent markers in the ASD genome-wide association study. Significance of associations between single nucleotide
polymorphisms and ASD range from 0.5 to 1 × 10
. Probability of association to be found at each individual variance level is denoted by Pvalue.
ASD, autism spectrum disorder; PRS, polygenic risk score.
ASD diagnosis in adults
pattern seen within mental health services, where diagnoses are
often clinical and diagnostic tool usage varies. By design our
control population did not have psychiatric comorbidities, and
this lack of control comorbidity data prevented comparative statis-
tical analysis. It is also likely that demographic data in this control
cohort are skewed by this lack of psychiatric comorbidity away
from the general population mean, which may inflate effect sizes.
All comorbid diagnoses were required to have been made by a
doctor, but were self-reported and therefore not standardised. As
a descriptive study we benefited from the large quantity and exten-
sive domains available from the NCMH data-set. Where possible,
results were elicited through subgroup analysis to reduce test
volume. Because of the number of variables tested, only the associ-
ation with not currently workingand off work because of sickness
or disablementwould remain significant following a conservative
Bonferroni correction. Associations here reported therefore
require further testing with a larger sample.
Implications for services
In this study we provide comorbidity rates and social demographic
information for adults presenting with ASD, with clinical utility for
consultations in adult ASD diagnostic services. Our findings suggest
that a majority of adults with ASD have psychiatric comorbidity
and should be appropriately screened and managed. Additionally,
clinicians should be aware of associated social demographic features,
including the high rates of alcohol problem use and being out of
work. Signposting toward, and integration with, third-sector organisa-
tions and services supporting adults with ASD is vital, and our results
may inform these services toward the possible difficulties some diag-
nosed with ASD in adulthood may face. The significantly increased
polygenic risk burden seen in our sample is a difficult concept to
convey in a clinical environment. It is likely that for some individuals,
genetic testing would provide an element of assurance and diagnostic
clarity, and our results may assist in genetic counselling. For many the
benefit of an ambiguous answer is questionable. This is an area where
future work with larger population sizes promises better results. Our
findings suggest that the polygenic risk burden is present in clinical
samples, and ongoing advances may allow us to explain this fully,
along with the associations and implications.
Jack F. G. Underwood, MBBS, PgCert, MRCPsych , Clinical Research Fellow,
Neuroscience and Mental Health Research Institute, Cardiff University, UK; Kimberley
M. Kendall, BSc Hons, MBBCh, MRCPsych, Wellcome Trust Clinical Research Fellow,
MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK;
Jennifer Berrett, BSc, MSc, Trainee Clinical Psychologist, Neuroscience and Mental
Health Research Institute, Cardiff University, UK; Catrin Lewis, BSc, PhD, Research
Associate, National Centre for Mental Health, Cardiff University, UK; Richard Anney,
BMedSc, PhD, Senior Lecturer (Bioinformatics), MRC Centre for Neuropsychiatric
Genetics and Genomics, Cardiff University, UK; Marianne B. M. van den Bree, BSc,
MSc, PhD, Professor of Psychological Medicine, MRC Centre for Neuropsychiatric
Genetics and Genomics, Cardiff University, UK; Jeremy Hall, MA, MBBChir, MPhil, PhD,
MRCPsych, Director and Research Theme Lead, Neuroscience and Mental Health
Research Institute, Cardiff University, UK
Correspondence: Dr Jack F. G. Underwood, Neuroscience & Mental Health Research
Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
First received 27 Jul 2018, final revision 19 Dec 2018, accepted 4 Jan 2019
Supplementary material
Supplementary material is available online at
We thank Professor Ian Jones along with the rest of the team at NCMH, the Bioinformatics team
at Cardiff University and all the staff at the Medical Research Council Centre for
Neuropsychiatric Genetics and Genomics (CNGG). The NCMH is a collaboration between
Cardiff, Swansea and Bangor Universities and is funded by the Welsh Government through
Health and Care Research Wales. We thank the NCMH study participants for their invaluable
contribution to this project.
This work was supported by the Wellcome Trust through an Institutional Strategic Support Fund
Clinical Primer Grant to J.F.G.U, and the Medical Research Council through the Mental Health
Data Pathfinder (MC_PC_17212) to J.H. and Cardiff University.
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ASD diagnosis in adults
... Studies of autism diagnosed in adulthood generally report a high frequency of comorbid psychiatric diagnoses (5)(6)(7)(8)(9). Another hypothesis therefore is that autism symptoms in childhood were mistaken as symptoms of other conditions (5,10) such as attention-de cit hyperactivity disorder (ADHD) (11,12) or obsessive-compulsive disorder (OCD)(13) due to symptom overlap. ...
... We found high incidences of ADHD, mood disorders, and anxiety before the age of 18, which is consistent with previous studies of comorbidity in individuals diagnosed with autism in adulthood (5)(6)(7)(8)(9)20). Incidences before the age of 12 were considerably lower, showing that most of the pre-autism diagnoses were given in adolescence. ...
... Sex differences of childhood prevalence were generally in the same direction as sex differences among the general population (Supplementary Table S1). We found a high incidence of stress disorders before the age of 18, particularly among females, whereas previous studies have either not reported rates of stress disorders(5-7) or only reported rates speci cally for post-traumatic stress disorder (8,9). ...
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Autism is a developmental condition, where symptoms are expected to occur in childhood, but a significant number of individuals are diagnosed with autism for the first time in adulthood. Here we use the National Danish Patient Registry to investigate diagnoses given in childhood among those that are diagnosed with autism in adulthood (N = 2199). We found that most childhood diagnoses were given after the age of 12, and attention-deficit hyperactivity disorder, affective disorders, anxiety, and stress disorders were the most prevalent childhood diagnoses. However, 69% of males and 61% of females with adult autism diagnoses had not received any of the included diagnoses before the age of 18. In most cases, the late autism diagnosis is therefore unlikely to be explained by either misdiagnosis or diagnostic overshadowing. This result is at odds with the prevailing notion that autistic symptoms tend to diminish with age. Therefore, further research is warranted to examine how early signs of autism may have manifested among these individuals, and how similar they are to autistic people diagnosed earlier in their development. Milder to moderate cases of psychiatric conditions that have been solely treated by family physician or school psychologists may not be fully included in our dataset.
... The longreported association between autism and epilepsy was examined by three reviews, with epilepsy co-occurring at prevalences of between 4.7% and 34.5%, dependent on sex and intellectual disability status (Lai, Lombardo, & Baron-Cohen, 2014;Rydzewska et al., 2021). Few reviews looked at co-occurrence of other neurological disorders such as migraine headache, which have potential pathophysiological overlap and where small clinical studies have previously shown associations (Underwood et al., 2019;Vetri, 2020). The aim of this study was therefore to report populationlevel estimates of prevalence in adults of psychiatric and selected neurological conditions in autistic individuals, and odds ratios relative to the general population using anonymised healthcare data. ...
... Cohort studies recruited from clinical environments suggest lifetime prevalence of psychosis in autism around 10-15%, though some smaller studies have suggested lower prevalence on clinical interview (Ghaziuddin & Zafar, 2008;Joshi et al., 2013;Stahlberg, Soderstrom, Rastam, & Gillberg, 2004;Underwood et al., 2019). Croen et al.'s 2015 analysis estimated the prevalence of schizophrenia at 8% in an autistic adult population (Croen et al., 2015), while Selten et al.'s 2015 study in Stockholm County, Sweden, found 0.6% of autistic youths (⩽17 years of age) had bipolar disorder and 0.6% non-affective psychotic disorder (Selten et al., 2015). ...
... However within the heterogeneity of autism presentations there appear to exist groups who are more at risk of substance or alcohol misuse, likely as selfmedication for anxiety or distressing experiences (Lai et al., 2014). Qualitative studies and those examining clinically-referred samples would appear to include these populations, with accompanying increase in observations of alcohol and substance abuse or misuse (Hofvander et al., 2009;Lai et al., 2014;Underwood et al., 2019). Our results are not consistent with this overall picture. ...
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Background Co-occurring psychiatric disorders are common in autism, with previous studies suggesting 54–94% of autistic individuals develop a mental health condition in their lifetime. Most studies have looked at clinically-recruited cohorts, or paediatric cohorts followed into adulthood, with less known about the autistic community at a population level. We therefore studied the prevalence of co-occurring psychiatric and neurological conditions in autistic individuals in a national sample. Methods This retrospective case-control study utilised the SAIL Databank to examine anonymised whole population electronic health record data from 2001 to 2016 in Wales, UK ( N = 3.6 million). We investigated the prevalence of co-occurring psychiatric and selected neurological diagnoses in autistic adults' records during the study period using International Classification of Diseases-10 and Read v2 clinical codes compared to general population controls matched for age, sex and deprivation Results All psychiatric conditions examined were more common amongst adults with autism after adjusting for age, sex and deprivation. Prevalence of attention-deficit hyperactivity disorder (7.00%), bipolar disorder (2.50%), obsessive-compulsive disorder (3.02%), psychosis (18.30%) and schizophrenia (5.20%) were markedly elevated in those with autism, with corresponding odds ratios 8.24–10.74 times the general population. Depression (25.90%) and anxiety (22.40%) were also more prevalent, with epilepsy 9.21 times more common in autism. Conclusions We found that a range of psychiatric conditions were more frequently recorded in autistic individuals. We add to understanding of under-reporting and diagnostic overshadowing in autism. With increasing awareness of autism, services should be cognisant of the psychiatric conditions that frequently co-occur in this population.
... Its cohort is the largest sample with phenotype data available to us, and a cross-disorder resource in itself. 36 As the NCMH is still being expanded by recruitment of participants, maximising its compatibility with DRAGON-Data was desired. Additionally, every core variable was required to be available in at least half of the current data-sets, taking into consideration that some data might be specific to child or adult cohorts. ...
Full-text available
Background: Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptoms and shared genetic liability is still poorly understood. Aims: Well-characterised, cross-disorder samples are needed to investigate this matter, but few currently exist. Our aim is to develop procedures to purposely curate and aggregate genotypic and phenotypic data in psychiatric research. Method: As part of the Cardiff MRC Mental Health Data Pathfinder initiative, we have curated and harmonised phenotypic and genetic information from 15 studies to create a new data repository, DRAGON-Data. To date, DRAGON-Data includes over 45 000 individuals: adults and children with neurodevelopmental or psychiatric diagnoses, affected probands within collected families and individuals who carry a known neurodevelopmental risk copy number variant. Results: We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all data-sets with genotype information have undergone rigorous quality control, imputation, copy number variant calling and polygenic score generation. Conclusions: DRAGON-Data combines genetic and non-genetic information, and is available as a resource for research across traditional psychiatric diagnostic categories. Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data-sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with Health Data Research UK.
... ASD is a usually lifelong, complex developmental disorder characterized by persistent difficulties with social communication and social interaction, and restricted, repetitive patterns of behavior causing important impairments in social or other functioning. ASD is therefore much broader than the pervasive developmental disorders in DSM-IV (62,63). ...
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Background Belgium is one of very few countries that legally allow euthanasia for suffering caused by psychiatric illness. In the first criminal trial in Belgium of physicians involved in euthanasia, three physicians recently faced the accusation of “murder by poisoning,” for allegedly having failed to comply with several requirements of the Belgian Euthanasia Law in granting the euthanasia request a woman suffering from psychiatric illness. Although all three physicians were acquitted, the case generated much debate among policy makers, medical professionals, and the general public. Method We use this trial as the starting point for a critical analysis of the adequacy of the three-level control system established in the Euthanasia Law, as it is applied in the evaluation of euthanasia requests from persons who suffer unbearably from a psychiatric illness. This analysis is based on information presented during the criminal trial as well as information on the euthanasia that was published in the press. Results Our analysis highlights substantial problems in the assessment and granting of the euthanasia request. The patient was euthanized without it having been substantiated that her psychiatric illness had no prospect of improvement and that her suffering could not be alleviated. The three-step control system enshrined in the Law and promoted by the Federal Control and Evaluation Commission for Euthanasia appears to have failed at each level. Conclusion To evaluate requests for euthanasia for mental suffering caused by psychiatric illness, the requirements of the Belgian Euthanasia Law should be complemented by mandating the advice of two psychiatrists, and face-to-face discussions between all physicians involved. In parallel with the process of evaluating the euthanasia request, a treatment track should be guaranteed where reasonable evidence-based treatments and recovery-oriented options are tried.
... In this way, persons with ADHD are more likely to experience headaches, but headaches may be present as a side effect of medications for ADHD; medications include methylphenidate, atomoxetine, and guanfacine [52•]. Comorbid migraine develops in 42.7% of adult ASD patients [53] and 28.4% of children [54]. In a study of 81 children with ASD [54], there were no differences in sex, age, or severity of autism. ...
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Purpose of Review The purpose of this review was to summarize current reports regarding emotional problems in children and adolescents with primary headaches. Emotional problems include those related to personality, psychiatric, and neurodevelopmental disorders. Recent Findings Alexithymia-like characteristics and internalized personality characteristics are considered to worsen primary headaches. Comorbid psychiatric traits such as depression and anxiety have been observed. When neurodevelopmental disorders coexist, it is necessary to pay attention not only to emotional problems but also to the side effects of concomitant drug and history of abuse. There are few reports with strong evidence for the pharmacological treatment of headaches accompanied by emotional problems. Summary Understanding emotional problems at an initial consultation and examining the application of psychotherapy could help improve the outcome of headaches in children and adolescents.
... Participants from 2 studies conducted within the Medical Research Council Centre for Neuropsychiatric Genetics and Genomics at Cardiff University were invited to take part: (1) the National Centre for Mental Health (NCMH) cohort study [18] and (2) the Cognition in Mood, Psychosis, and Schizophrenia Study (CoMPaSS) [19]. Diagnoses were ascertained through either self-report in the NCMH or through a clinical interview in the CoMPaSS (Schedule for Clinical Assessment in Neuropsychiatry [20]). ...
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Background Cognitive impairments are features of many psychiatric disorders and affect functioning. A barrier to cognitive research on psychiatric disorders is the lack of large cross-disorder data sets. However, the collection of cognitive data can be logistically challenging and expensive. Web-based collection may be an alternative; however, little is known about who does and does not complete web-based cognitive assessments for psychiatric research. Objective The aims of this study are to develop a web-based cognitive battery for use in psychiatric research, validate the battery against the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and compare the characteristics of the participants who chose to take part with those of the individuals who did not participate. Methods Tasks were developed by The Many Brains Project and selected to measure the domains specified by the MATRICS initiative. We undertook a cross-validation study of 65 participants with schizophrenia, bipolar disorder, depression, or no history of psychiatric disorders to compare the web-based tasks with the MATRICS Consensus Cognitive Battery. Following validation, we invited participants from 2 large ongoing genetic studies, which recruited participants with psychiatric disorders to complete the battery and evaluated the demographic and clinical characteristics of those who took part. Results Correlations between web-based and MATRICS tasks ranged between 0.26 and 0.73. Of the 961 participants, 887 (92.3%) completed at least one web-based task, and 644 (67%) completed all tasks, indicating adequate completion rates. Predictors of web-based participation included being female (odds ratio [OR] 1.3, 95% CI 1.07-1.58), ethnicity other than White European (OR 0.66, 95% CI 0.46-0.96), higher levels of education (OR 1.19, 95% CI 1.11-1.29), diagnosis of an eating disorder (OR 2.17, 95% CI 1.17-4) or depression and anxiety (OR 5.12, 95% CI 3.38-7.83), and absence of a diagnosis of schizophrenia (OR 0.59, 95% CI 0.35-0.94). Lower performance on the battery was associated with poorer functioning (B=−1.76, SE 0.26; P<.001). Conclusions Our findings offer valuable insights into the advantages and disadvantages of testing cognitive function remotely for mental health research.
... The NCMH is a Welsh Government-funded research centre that investigates neurodevelopmental, psychiatric and neurodegenerative disorders across the lifespan. Its cohort is the largest sample with phenotype data available to us, and a cross-disorder resource in itself 29 . As NCMH is still being expanded by recruitment of participants, maximising its compatibility with DRAGON-Data was desired. ...
Full-text available
Introduction Current psychiatric diagnoses, although heritable, have not been clearly mapped onto distinct underlying pathogenic processes. The same symptoms often occur in multiple disorders, and a substantial proportion of both genetic and environmental risk factors are shared across disorders. However, the relationship between shared symptomatology and shared genetic liability is still poorly understood. Well-characterised, cross-disorder samples are needed to investigate this matter, but currently few exist, and severe mental disorders are poorly represented in existing biobanking efforts. Purposely curated and aggregated data from individual research groups can fulfil this unmet need, resulting in rich resources for psychiatric research. Methods and analyses As part of the Cardiff MRC Mental Health Data Pathfinder, we have curated and harmonised phenotypic and genetic information from 15 studies within the MRC Centre for Neuropsychiatric Genetics and Genomics to create a new data repository, DRAGON-DATA. To date, DRAGON-DATA includes over 45,000 individuals: adults or children with psychiatric diagnoses, affected probands with family members and individuals who carry a known neurodevelopmental copy number variant (ND-CNV). We have processed the available phenotype information to derive core variables that can be reliably analysed across groups. In addition, all datasets with genotype information have undergone rigorous quality control, imputation, CNV calling and polygenic score generation. Ethics and Dissemination DRAGON-DATA combines genetic and non-genetic information and is available as a resource for research across traditional psychiatric diagnostic categories. Its structure and governance follow standard UK ethical requirements (at the level of participating studies and the project as a whole) and conforms to principles reflected in the EU data protection scheme (GDPR). Algorithms and pipelines used for data harmonisation are currently publicly available for the scientific community, and an appropriate data sharing protocol will be developed as part of ongoing projects (DATAMIND) in partnership with HDR UK.
... Psychiatric comorbidity in ASD is common, with lifetime prevalence of over 70%, incidence well over 50% (Buck et al., 2014;Gillberg & Billstedt, 2000;Gillberg et al., 2016;Underwood et al., 2019;Vohra et al., 2017), compared to the general population. In the Swedish general population, the incidence of self-reported psychiatric problems was 17% in 2018, according to a report from the Swedish Public Health Authority released in 2020 (Swedish Public Health Authority, 2020). ...
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Relatively little has been published about the prevalence of autism in adults with psychiatric disorders. In this study, all new patients referred to an adult psychiatric outpatient clinic in Sweden between November 2019 and October 2020 (n = 562) were screened for autism spectrum disorders using the Ritvo Autism and Asperger Diagnostic Scale Screen (RAADS-14). Out of the 304 (58%) responders, 197 who scored above the cut off (14) were invited to participate in an in-depth assessment. Twenty-six of the 48 that participated in the assessment met criteria for ASD and an additional eight had subthreshold ASD symptoms. We estimated the prevalence of ASD in this population to at least 18.9%, with another 5–10% having subthreshold symptoms.
Individuals with intellectual disability and/or autism spectrum disorder experience healthcare inequalities and have more unmet healthcare needs than the general population. Despite this, there is a sparsity of literature exploring the views of individuals with autism spectrum disorder and/or intellectual disability. This article summarises and evaluates an integrated review that explores the barriers and facilitators those with intellectual disability and/or autism spectrum disorder face when accessing primary healthcare.
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The concept of “acquired autism” refers to the hypothesis that amongst the massive heterogeneity that encompasses autism spectrum disorder (ASD) there may be several phenotypes that are neither syndromic nor innate. Strong and consistent evidence has linked exposure to various pharmacological and infective agents with an elevated risk of a diagnosis of ASD including maternal valproate use, rubella and herpes encephalitis. Autoimmune encephalitis (AE) describes a group of conditions characterised by the body's immune system mounting an attack on healthy brain cells causing brain inflammation. The resultant cognitive, psychiatric and neurological symptoms that follow AE have also included ASD or autism-like traits and states. We review the current literature on AE and ASD. Drawing also on associated literature on autoimmune psychosis (AP) and preliminary evidence of a psychosis-linked subtype of ASD, we conclude that AE may either act as a potentially causative agent for ASD, and/or produce symptoms that could easily be mistaken for or misdiagnosed as autism. Further studies are required to discern the connection between AE and autism. Where autism is accompanied by regression and atypical onset patterns, it may be prudent to investigate whether a differential diagnosis of AE would be more appropriate.
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Background: Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods: We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). Results: Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). Conclusions: Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
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Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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Background: Major depressive disorder (MDD) is a disabling mood disorder, and despite a known heritable component, a large meta-analysis of genome-wide association studies revealed no replicable genetic risk variants. Given prior evidence of heterogeneity by age at onset in MDD, we tested whether genome-wide significant risk variants for MDD could be identified in cases subdivided by age at onset. Methods: Discovery case-control genome-wide association studies were performed where cases were stratified using increasing/decreasing age-at-onset cutoffs; significant single nucleotide polymorphisms were tested in nine independent replication samples, giving a total sample of 22,158 cases and 133,749 control subjects for subsetting. Polygenic score analysis was used to examine whether differences in shared genetic risk exists between earlier and adult-onset MDD with commonly comorbid disorders of schizophrenia, bipolar disorder, Alzheimer's disease, and coronary artery disease. Results: We identified one replicated genome-wide significant locus associated with adult-onset (>27 years) MDD (rs7647854, odds ratio: 1.16, 95% confidence interval: 1.11-1.21, p = 5.2 × 10(-11)). Using polygenic score analyses, we show that earlier-onset MDD is genetically more similar to schizophrenia and bipolar disorder than adult-onset MDD. Conclusions: We demonstrate that using additional phenotype data previously collected by genetic studies to tackle phenotypic heterogeneity in MDD can successfully lead to the discovery of genetic risk factor despite reduced sample size. Furthermore, our results suggest that the genetic susceptibility to MDD differs between adult- and earlier-onset MDD, with earlier-onset cases having a greater genetic overlap with schizophrenia and bipolar disorder.
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High-throughput data production technologies, particularly ‘next-generation’ DNA sequencing, have ushered in widespread and disruptive changes to biomedical research. Making sense of the large datasets produced by these technologies requires sophisticated statistical and computational methods, as well as substantial computational power. This has led to an acute crisis in life sciences, as researchers without informatics training attempt to perform computation-dependent analyses. Since 2005, the Galaxy project has worked to address this problem by providing a framework that makes advanced computational tools usable by non experts. Galaxy seeks to make data-intensive research more accessible, transparent and reproducible by providing a Web-based environment in which users can perform computational analyses and have all of the details automatically tracked for later inspection, publication, or reuse. In this report we highlight recently added features enabling biomedical analyses on a large scale.
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In the last 30 years, twin studies have indicated a strong genetic contribution to Autism Spectrum Disorders (ASD). The heritability of ASD is estimated to be 50 %, mostly captured by still unknown common variants. In approximately 10 % of patients with ASD, especially those with intellectual disability, de novo copy number or single nucleotide variants affecting clinically relevant genes for ASD can be identified. Given the function of these genes, it was hypothesized that abnormal synaptic plasticity and failure of neuronal/synaptic homeostasis could increase the risk of ASD. In parallel, abnormal levels of blood serotonin and melatonin were reported in a subset of patients with ASD. These biochemical imbalances could act as risk factors for the sleep/circadian disorders that are often observed in individuals with ASD. Here, we review the main pathways associated with ASD, with a focus on the roles of the synapse and the serotonin-NAS-melatonin pathway in the susceptibility of ASD.
Adults with autism spectrum disorder (ASD) are thought to be at disproportionate risk of developing mental health comorbidities, with anxiety and depression being considered most prominent amongst these. Yet, no systematic review has been carried out to date to examine rates of both anxiety and depression focusing specifically on adults with ASD. This systematic review and meta-analysis examined the rates of anxiety and depression in adults with ASD and the impact of factors such as assessment methods and presence of comorbid intellectual disability (ID) diagnosis on estimated prevalence rates. Electronic database searches for studies published between January 2000 and September 2017 identified a total of 35 studies, including 30 studies measuring anxiety ( n = 26 070; mean age = 30.9, s.d. = 6.2 years) and 29 studies measuring depression ( n = 26 117; mean age = 31.1, s.d. = 6.8 years). The pooled estimation of current and lifetime prevalence for adults with ASD were 27% and 42% for any anxiety disorder, and 23% and 37% for depressive disorder. Further analyses revealed that the use of questionnaire measures and the presence of ID may significantly influence estimates of prevalence. The current literature suffers from a high degree of heterogeneity in study method and an overreliance on clinical samples. These results highlight the importance of community-based studies and the identification and inclusion of well-characterized samples to reduce heterogeneity and bias in estimates of prevalence for comorbidity in adults with ASD and other populations with complex psychiatric presentations.
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable penetrance and genetic pleiotropy are pervasive characteristics of autism genetics. Although this advancing insight should improve clinical care, at present there is a substantial discrepancy between research knowledge and its clinical application. In this Review, we discuss the current challenges and opportunities for the translation of autism genetics knowledge into clinical practice.
Background: The UK Biobank is a unique resource for biomedical research, with extensive phenotypic and genetic data on half a million adults from the general population. We aimed to examine the effect of neurodevelopmental copy number variants (CNVs) on the cognitive performance of participants. Methods: We used Affymetrix Power Tools and PennCNV-Affy software to analyze Affymetrix microarrays of the first 152,728 genotyped individuals. We annotated a list of 93 CNVs and compared their frequencies with control datasets. We analyzed the performance on seven cognitive tests of carriers of 12 CNVs associated with schizophrenia (n = 1087) and of carriers of another 41 neurodevelopmental CNVs (n = 484). Results: The frequencies of the 93 CNVs in the Biobank subjects were remarkably similar to those among 26,628 control subjects from other datasets. Carriers of schizophrenia-associated CNVs and of the group of 41 other neurodevelopmental CNVs had impaired performance on the cognitive tests, with nine of 14 comparisons remaining statistically significant after correction for multiple testing. They also had lower educational and occupational attainment (p values between 10(-7) and 10(-18)). The deficits in cognitive performance were modest (Z score reductions between 0.01 and 0.51), compared with individuals with schizophrenia in the Biobank (Z score reductions between 0.35 and 0.90). Conclusions: This is the largest study on the cognitive phenotypes of CNVs to date. Adult carriers of neurodevelopmental CNVs from the general population have significant cognitive deficits. The UK Biobank will allow unprecedented opportunities for analysis of further phenotypic consequences of CNVs.
Autism is a complex disease with many genetic factors contributing to the variable phenotype presentation. Genome-wide association studies (GWAS) using large cohorts and dense datasets have revealed a myriad of genes implicated in autism. Several of these genes belong to common biological pathways and gene networks that converge on potential therapeutic targets. In this regard, CACNA, GRM, CNTN, ubiquitin, and SLIT gene families have shown promising variants in association with autism and related neurodevelopmental disorders. Both common and rare variants reside on these genes discovered primarily by single nucleotide polymorphism (SNP) arrays and whole exome sequencing. The ability to examine large cohorts through unbiased screening and statistical testing of allele frequencies between cases, families, and controls through GWAS will continue to elucidate and clarify the puzzle of autism and inform clinical care.