Article

Characteristics and Concordance of Autism Spectrum Disorders Among 277 Twin Pairs

Department of Medical Informatics, Kennedy Krieger Institute, Baltimore, MD 21211, USA.
JAMA Pediatrics (Impact Factor: 7.15). 10/2009; 163(10):907-14. DOI: 10.1001/archpediatrics.2009.98
Source: PubMed

ABSTRACT

To examine patterns of autism spectrum disorder (ASD) inheritance and other features in twin pairs by zygosity, sex, and specific ASD diagnosis.
Cross-sectional study.
Internet-based autism registry for US residents.
Survey results from 277 twin pairs (210 dizygotic [DZ] and 67 monozygotic [MZ]) aged 18 years or younger with at least 1 affected twin.
Zygosity and sex.
Concordance within twin pairs of diagnosis, natural history, and results from standardized autism screening.
Pairwise ASD concordance was 31% for DZ and 88% for MZ twins. Female and male MZ twins were 100% and 86% concordant, respectively, and DZ twin pairs with at least 1 female were less likely to be concordant (20%) than were male-male DZ twin pairs (40%). The hazard ratio for ASD diagnosis of the second twin after a first-twin diagnosis was 7.48 for MZ vs DZ twins (95% confidence interval, 3.8-14.7). Affected DZ individual twins had an earlier age at first parental concern and more frequent diagnoses of intellectual disability than did MZ twins; MZ twins had a higher prevalence of bipolar disorder and Asperger syndrome and higher concordance of the latter. Results of autism screening correlated with parent-reported ASD status in more than 90% of cases.
Our data support greater ASD concordance in MZ vs DZ twins. Overall higher functioning, psychiatric comorbidity, and Asperger syndrome concordance among affected MZ vs DZ twins may also suggest differential heritability for different ASDs. For families in which one MZ twin is diagnosed with ASD, the second twin is unlikely to receive an ASD diagnosis after 12 months. In addition, Internet parent report of ASD status is valid.

Full-text

Available from: Rebecca E Rosenberg, Oct 15, 2015
ARTICLE
Characteristics and Concordance of Autism
Spectrum Disorders Among 277 Twin Pairs
Rebecca E. Rosenberg, MD, MPH; J. Kiely Law, MD, MPH; Gayane Yenokyan, MS;
John McGready, PhD; Walter E. Kaufmann, MD; Paul A. Law, MD, MPH
Objectives: To examine patterns of autism spectrum
disorder (ASD) inheritance and other features in twin pairs
by zygosity, sex, and specific ASD diagnosis.
Design: Cross-sectional study.
Setting: Internet-based autism registry for US residents.
Participants: Survey results from 277 twin pairs (210
dizygotic [DZ] and 67 monozygotic [MZ]) aged 18 years
or younger with at least 1 affected twin.
Main Exposures: Zygosity and sex.
Outcome Measures: Concordance within twin pairs
of diagnosis, natural history, and results from standard-
ized autism screening.
Results: Pairwise ASD concordance was 31% for DZ and
88% for MZ twins. Female and male MZ twins were 100%
and 86% concordant, respectively, and DZ twin pairs with
at least 1 female were less likely to be concordant (20%)
than were male-male DZ twin pairs (40%). The hazard
ratio for ASD diagnosis of the second twin after a first-
twin diagnosis was 7.48 for MZ vs DZ twins (95% con-
fidence interval, 3.8-14.7). Affected DZ individual twins
had an earlier age at first parental concern and more fre-
quent diagnoses of intellectual disability than did MZ
twins; MZ twins had a higher prevalence of bipolar dis-
order and Asperger syndrome and higher concordance
of the latter. Results of autism screening correlated with
parent-reported ASD status in more than 90% of cases.
Conclusions: Our data support greater ASD concordance
in MZ vs DZ twins. Overall higher functioning, psychiat-
ric comorbidity,and Asperger syndrome concordance among
affected MZ vs DZ twins may also suggest differential heri-
tability for different ASDs. For families in which one MZ
twin is diagnosed with ASD, the second twin is unlikely to
receive an ASD diagnosis after 12 months. In addition, In-
ternet parent report of ASD status is valid.
Arch Pediatr Adolesc Med. 2009;163(10):907-914
A
LTHOUGH DIAGNOSES OF
autism spectrum disor-
ders (ASDs) are increas-
ing in the United States,
the genetic and environ-
mental bases of these heritable
1
(85%)
yet heterogeneous neuropsychiatric dis-
orders still are not well understood.
2-7
In
this article, ASD refers to a subset of the
pervasive developmental disorders de-
scribed in the Diagnostic and Statistical
Manual of Mental Disorders (Fourth Edi-
tion, Text Revision) (DSM-IV-TR).
8
Only 10% of ASD cases can be directly
attributed to an underlying medical con-
dition, such as fragile X syndrome,
9
and id-
iopathic autism is likely caused by a com-
bination of genetic and environmental
factors.
9-12
Although molecular genetic re-
search has made some advances among
ASD multiplex families in elucidating spe-
cific genetic linkages,
6
there have been few
ASD twin studies.
9-11,13
To our knowledge,
only 5 epidemiologically based, distinct
twin samples with at least 1 autistic pro-
band have been described since 1977, and
all described fewer than 50 twin pairs
14-19
;
pairwise monozygotic (MZ) concordance
for ASD ranges from 36% to 95% and di-
zygotic concordance (DZ) from 0% to 23%.
Recently, the Interactive Autism Net-
work (IAN) was developed as an online
community within a research frame-
work, in part to reduce the challenges of
recruiting participants with autism. The
IAN may now represent the largest re-
search cohort of twins with at least 1 pro-
band with ASD (N=277). In this study of
data from the IAN, we test 4 hypotheses.
First, although this is not an epidemio-
logic sample, we expect that the rates of
concordance among MZ and DZ twin pairs
will be consistent with past population-
based studies. In comparing MZ and DZ
concordant pairs, we anticipate there will
be significantly more homogeneity in the
presentation, natural history, and medi-
cal history among MZ pairs, including age
Author Affiliations:
Department of Medical
Informatics (Drs Rosenberg,
J. K. Law, and P. A. Law) and
Center for Genetic Disorders of
Cognition and Behavior,
Kennedy Krieger Institute
(Dr Kaufmann), The Johns
Hopkins Medical Institutions;
Departments of Pediatrics
(Drs J. K. Law and P. A. Law)
and Psychiatry, Neurology,
Pathology, and Radiology
(Dr Kaufmann),
The Johns Hopkins University
School of Medicine; and
Department of Biostatistics,
Bloomberg School of Public
Health, The Johns Hopkins
University (Ms Yenokyan
and Dr McGready),
Baltimore, Maryland.
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at diagnosis and Social Communication Questionnaire
(SCQ)
20
and Social Responsiveness Scale (SRS)
21
scores.
Second, we hypothesize that, given the heterogeneous
causes of ASD and the complex interplay between ge-
netics and the environment, affected DZ and MZ twins
may have different disease characteristics and natural his-
tories.
22-24
Third, considering that genetic contributions
to specific components of the 3 ASDs appear to dif-
fer,
25,26
we anticipate that ASD diagnostic concordance will
also differ by sex.
19,23,27
Fourth, we will demonstrate the
utility of the IAN as a new twin registry for autism, which
can provide unique knowledge because of its large sample
size. By using data from parent-completed question-
naires, including SCQ and SRS scores, we will demon-
strate that parent-reported ASD data are a reasonable proxy
for determining ASD status.
22,27-29
METHODS
PARTICIPANTS
The IAN is an online, US-based research database begun in April
2, 2007, with more than 25 000 individuals enrolled, includ-
ing 9000 children with an ASD and their immediate family mem-
bers. The database is continually updated, recruitment is on-
going, and all data are voluntarily submitted by families. A pilot
phase of data collection began on September 11, 2006, and the
current analysis was conducted with data received as of
12:34
PM on July 15, 2008. The IAN is an open resource, with
deidentified data made available to other research groups.
Of registered respondents with ASD, all self-identified twins
were selected. Multiple births beyond twins were excluded. The
IAN includes family members without ASD, and any twin pairs
in which neither twin is identified as having an ASD were elimi-
nated (
Figure 1). Twins with diagnoses of autistic disorder
(AD), pervasive developmental disorder, not otherwise speci-
fied (PDD-NOS), and Asperger syndrome (AS) were included;
respondents choosing a diagnosis of ASD or PDD were in-
cluded in the category “other ASDs.” Rett syndrome is an ex-
clusion criterion for registering with IAN, and respondents with
childhood disintegrative disorder were excluded from this analy-
sis. Data from twins who met inclusion criteria were then linked
to data from their co-twins, both affected and unaffected. Fami-
lies with at least 1 affected twin received an e-mail message in
May 2008 asking them to complete any unfinished IAN ques-
tionnaires, particularly the child profile form.
Demographic and other general characteristics of the study
sample are provided in
Table 1. Options for race/ethnicity were
provided by the registry; parents could decline to answer or could
report 1 or more races.
QUESTIONNAIRES AND SCREENING
The IAN Project data collection consists of multiple topic-
specific questionnaires, authored by the IAN research team in
collaboration with other researchers, and 2 standardized in-
struments (SCQ and SRS) commonly used in ASD research.
IAN Questionnaires
All families complete the initial registration forms and are then
invited to complete several other questionnaires, including a
profile for each affected child and his/her siblings; once regis-
tered, families receive reminders every 2 weeks to complete out-
standing questionnaires. These questionnaires were devel-
oped by IAN staff in collaboration with members of the IAN
Science Advisory Committee and were tested during pilot stud-
ies and revised as needed. All participants completed a second-
generation version of the questionnaire (Figure 1).
Participants were categorized as having an intellectual dis-
ability (ID) if they reported either a diagnosis of mental retar-
dation or an IQ score of less than 70.
Social Responsiveness Scale
The SRS (Western Psychological Services, Los Angeles, Cali-
fornia) is a validated, 65-item, parent/teacher-completed, norm-
referenced screening tool designed to differentiate between in-
dividuals with ASD and those without ASD and/or with other
psychiatric conditions, primarily by examining social deficits,
in particular, social reciprocity.
21,30
Clinical t score screening
categories of less than 55, 55 to 59, 60 to 75, and more than 75
suggest likely unaffected status and borderline, mild to mod-
erate, or severe autistic features, respectively. The SRS parent
form was included for all IAN participants aged 4 to 18 years
as of February 26, 2008.
Social Communication Questionnaire
The SCQ,
20
originally called the Autism Screening Question-
naire, is a widely used, dichotomous autism screening tool con-
sisting of 40 items based on DSM-IV-TR criteria for ASDs and
the Autism Diagnostic Interview–Revised (Western Psycho-
logical Services). A t score of 15 or more is suggestive of ASDs.
For clinical use, the SCQ cutoff score for marked verbal im-
pairment for siblings of affected children is 12 or higher to ad-
just for the increased probability that they have ASD. The SCQ,
lifetime version, was made available to all IAN participants aged
2 to 18 years as of April 2, 2007.
DATA COLLECTION
Electronic consent was elicited from participating families un-
der the auspices of The Johns Hopkins Medicine Institutional Re-
Sets of multiples with
at least 1 affected proband
283
Total twin pairs
277
Sets of triplets dropped6
210 (75.8%) Pairs
97 MM
23 FF
90 MF
58 MM
9 FF
67 (24.2%) Pairs
Pairs (348 individuals)
completed CHF
162
Pairs (142 individuals)
completed SRS†
64
Pairs (366 individuals)
completed SCQ
173
Pairs (81 individuals)
completed CHF
36
Pairs (37 individuals)
completed SRS†
17
Pairs (88 individuals)
completed SCQ
37
Figure 1. Participant inclusion and comparison of form completion by twin
type. CHF indicates child history form; FF, female-female; MF, male-female;
MM, male-male; SCQ, Social Communication Questionnaire; and SRS, Social
Responsiveness Scale. *
2
P .05 for dizygotic (DZ) and monozygotic (MZ)
twin pairs and individual form completion. †Completion among eligible (age
4 years) participants only. A total of 190 MZ and 57 DZ twin pairs had
access to the SRS.
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view Boards. All survey data were entered by parents and main-
tained in the Internet-Mediated Research System (Medical Decision
Logic, Inc, Baltimore, Maryland). If families skipped a question
based on an answer to the previous question, answered “don’t
know,” or declined to answer a question, data were recorded as
missing. All analyses are based on nonmissing data.
STATISTICAL ANALYSIS
For descriptive analysis, comparison between MZ and DZ twin
pairs was performed at both the pair and individual levels based
on available data using the paired t test and
2
proportion test.
To compare twin-type distribution with population averages,
Table 1. Demographic and Natural History Characteristics of 554 Individual Twins and 277 Twin Pairs
a
DZ Twins MZ Twins All Twin Pairs
No. of twin pairs 210 67 277
Mean (SD) age, y 7.6 (3.5) 7.8 (3.6) 7.7 (3.5)
Race
b
White 194 (92.4) 64 (95.5) 258 (93.1)
Black/African American 9 (4.3) 1 (1.5) 10 (3.6)
Native Hawaiian/Pacific Islander 1 (0.5) 0 1 (0.4)
Asian 6 (2.9) 2 (3.0) 8 (2.9)
American Indian/Alaskan Native 1 (0.5) 0 1 (0.4)
Other 6 (2.9) 2 (3.0) 8 (2.9)
Unknown 0 0 0
Ethnicity
Hispanic (207 DZ and 67 MZ pairs) 8 (3.9) 7 (10.5) 15 (5.4)
Total individual twins 420 134 554
Male sex 284 (67.6) 116 (86.6) 400 (72.2)
Individuals with ASDs
b
274 (65.2) 126 (94.0) 400 (72.2)
Autism 155 (56.6) 68 (54.0) 223 (55.8)
PDD-NOS 61 (22.3) 29 (23.0) 46 (22.5)
Asperger syndrome 26 (9.5) 20 (15.9) 90 (11.5)
Other 32 (11.7) 9 (7.1) 41 (10.3)
Natural/medical history, No. of co-twins with ASD 274 126 400
Male sex 220 (80.3) 108 (85.7) 329 (82.3)
With completed forms 203 (74.1) 73 (58.0) 276 (69.0)
Severe prematurity, 34-wk gestational age (n=265) 39/196 (19.9) 18/69 (26.1) 57 (21.5)
Mean (SD) age at diagnosis, mo (n=274) 37.8 (21.3) 38.1 (17.6) 37.9 (20.4)
Age at which parents were first concerned (n=273),
b
mo 202 72 274
0-17 113 (55.9) 29 (40.3) 149 (51.8)
18 89 (44.1) 43 (59.7) 139 (48.2)
Any skills lost 74 (36.5) 25 (34.3) 99 (35.9)
Loss of social or communication skills at age 3y
c
60 (29.6) 20 (27.4) 80 (29.1)
Educational level
Any special education (n=248) 150/183 (82.0) 48/65 (73.9) 198 (79.8)
Has aide (n=270) 104 (52.5) 32 (44.4) 136 (50.4)
Comorbidities per parent report
“Mental retardation”/ intellectual disability (n=274)
d
51/201 (25.4) 12/73 (16.4) 64 (23.0)
Attention-deficit/hyperactivity disorder 40 (19.7) 15 (20.6) 55 (19.9)
Bipolar disorder
d
3 (1.5) 4 (5.5) 7 (3.5)
Anxiety disorder 26 (12.3) 9 (12.3) 36 (13.0)
Seizures/epilepsy 13 (6.4) 4 (5.5) 17 (6.2)
SCQ, Affected twins
Completed SCQ 223/274 (81.4) 81/126 (64.3) 304/400 (76.0)
Positive results
Cutoff score 15 for all 202 (90.6) 72 (89.0) 274 (90.1)
Cutoff score 15; 13 if sibling 212 (95.1) 77 (95.1) 289 (95.1)
SRS, Affected twins
Completed SRS/No. eligible (% completing SRS)
e
81/250 (32.4) 32/107 (29.9) 113/357 (31.7)
Mean (SD) t score 86.0 (16.2) 81.6 (13.9) 84.8 (15.6)
Category
Severe 59 (72.8) 20 (62.5) 79 (69.9)
Mild to moderate 18 (22.2) 11 (34.4) 29 (25.7)
Borderline 3 (3.7) 0 3 (2.7)
Likely unaffected 1 (1.2) 1 (3.3) 2 (1.8)
Abbreviations: ASD, autism spectrum disorder; DZ, dizygotic; MZ, monozygotic; PPD-NOS, pervasive developmental disorder, not otherwise specified;
SCQ, Social Communication Questionnaire; SRS, Social Responsiveness Scale.
a
Data are given as number (percentage) of participants unless otherwise indicated. For “Race/Ethnicity,” parents could report 1 or more races.
b
P .05.
c
A total of 24 children were younger than 3 years when data were collected and thus were still at risk for loss of skills.
d
P .10.
e
For the SRS, participants are eligible if aged 4 years or older; SRS was made available to Interactive Autism Network families in February 2008. Categories
based on t score were defined as: likely unaffected, 55; borderline, 55-59; mild to moderate, 60-75; severe, 75.
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the 2-sample test of proportions was used. To assess the valid-
ity of parent-reported ASD among children enrolled in IAN,
available SRS and SCQ scores for all affected and nonaffected
twins were analyzed using published cutoff points for binary
designation of ASD status and compared using interrater
agreement.
Pairwise and probandwise
31
concordance was calculated using
unweighted and weighted
2
analysis, respectively, assuming an
ascertainment ratio of 1.0. For exact diagnosis concordance, we
considered collapsing the “other ASD” category with PDD-
NOS. However, there were significant differences in the propor-
tion of positive SCQ screening results and mean age at diagno-
sis between these groups, suggesting real differences; therefore,
we were unable to combine them (data not shown).
A nonparametric Kaplan-Meier procedure was used to es-
timate the diagnosis-free time for twin B, using the lag time be-
tween diagnosis of twin A and twin B (twin A was defined as
the first diagnosed twin; if both twins were diagnosed simul-
taneously, twin A status was assigned to the first twin regis-
tered in the IAN). In addition, the association between the risk
of diagnosis in twin B and type of twin (MZ or DZ) was as-
sessed using a semiparametric Cox proportional hazards model.
Data from twin pairs with completed forms were com-
pared using
2
analysis and Fisher exact 1- and 2-tailed tests
(categorical variables) or a t test weighted for unequal vari-
ance (continuous variables). Analyses were completed using
STATA statistical software, version 9.2 (STATACorp, College
Station, Texas) on the live database.
RESULTS
Racial/ethnic, age, and sex distributions were similar for
DZ and MZ twin pairs, although whites are overrepre-
sented in the entire sample. Overall, MZ pairs consti-
tuted 25% of the total twin sample (Table 1). Signifi-
cantly fewer child profiles were completed for MZ than
for DZ twins; logistic regression suggested that pres-
ence of concordance was the determining factor for in-
complete child profile forms (data not shown). Among
affected individual twins, significantly more DZ partici-
pants reported a diagnosis of “other ASD,” and more MZ
participants reported having AS (Table 1). Parents of af-
fected DZ individuals were significantly more likely
(44.1%) to first become concerned before the child
reached age 18 months, compared with those with MZ
twins (59.7%; P=.02). In addition, DZ twins were more
likely to report diagnoses of ID (by parent report or IQ
score) (P=.12) and less likely to report having bipolar
disorder (P= .06). Among affected twins, there was no
difference in SRS or SCQ score distribution or screening
results between twin types.
Table 2 shows that concordance was significantly
higher among MZ twins than DZ twins. Given the as-
sumption that PDD-NOS is a milder form of AD, but mark-
edly different from AS, we labeled twin pairs as severity
concordant if both twins had AD and/or PDD-NOS or if
both twins had AS; otherwise, twins were considered dis-
cordant (103 pairs). Among ASD-concordant pairs with
a DSM-IV-TR diagnosis, significantly more MZ pairs than
DZ pairs (96.1% vs 80.8%) were severity concordant
(P=.02). This difference was mainly because of the higher
prevalence and concordance of AS among MZ twins.
Table 3 demonstrates that there were no female-
female MZ twins diagnosed as having AS. Among male-
male twin pairs, 58 (14%) MZ and 97 (2%) DZ pairs were
AS concordant, although there was no significant differ-
ence in the proportion of AS diagnoses in twin A (6/31
vs 8/43; P= .93). Further analysis of differences by zy-
gosity found that, among DZ pairs, having at least 1 fe-
male conferred a significantly decreased risk (P.01) of
concordance (relative risk, 0.55; 95% confidence inter-
val [CI], 0.36-0.84). The adjusted relative risk ratio (0.70)
for concordance by twin type (DZ:MZ) was signifi-
cantly different for pairs with at least 1 female member
compared with male-male twins (P.001; 95% CI, 0.36-
0.84).
Figure 2 shows that, among concordant twins with
a known age at diagnosis, MZ co-twins had a signifi-
cantly higher risk than DZ cotwins (hazard ratio,7.5;
95% CI, 3.8-14.7; P .001). By approximately 3 months
after the twin A diagnosis, the proportion of autism di-
agnoses for twin B was 51% for MZ twins and 94% for
DZ twins. Mean time between diagnosis of twin A and
twin B among concordant pairs was 5.0 months (95%
CI, 1.5-8.5) and 1.8 months (95% CI, 0.6-3.0) for DZ
and MZ pairs, respectively (P=.08; 95% CI, 0.41-6.91)
(Figure 2).
Table 4 demonstrates that, among concordant pairs
who completed child profile forms (59 pairs), DZ twins
were significantly more discordant for lost skills. In ad-
dition, a trend was seen for DZ twins being more discor-
dant for ID, timing of developmental milestones, and spe-
cific early skill loss.
There was no significant difference in SRS or SCQ
scores between DZ vs MZ twins (
Table 5). For SRS and
SCQ (cutoff score, 15) screening tests, percentage agree-
ment with reported ASD status was 92.1% ( =0.8); for
the SCQ with the adjusted cutoff point (see the “Social
Communication Questionnaire” subsection in the “Meth-
ods” section), agreement and were even higher (94%
and 0.88, respectively). Among reportedly unaffected
twins, 9 of 150 (6.0%) and 9 of 66 (13.6%) had positive
results on the SCQ and SRS, respectively; of reportedly
affected twins, 14 (5%) and 5 (4.4%) had negative re-
sults from SCQ and SRS, respectively.
Table 2. ASD Concordance Among All Twin Pairs
by Twin Type
a
DZ Twins MZ Twins
No. of pairs 210 67
Pairwise concordance
b
64 (30.5) 59 (88.1)
Probandwise concordance,
b
% 46.7 93.7
Total No. of concordant pairs
c,d
52 51
Diagnosis
Autism/PDD-NOS for both twins 40 (76.9) 42 (82.4)
Asperger syndrome for both twins 2 (3.9) 7 (13.7)
Autism/PDD-NOS and Asperger syndrome 10 (19.2) 2 (3.9)
Abbreviations: ASD, autism spectrum disorder; DZ, dizygotic;
MZ, monozygotic; PPD-NOS, pervasive developmental disorder, not
otherwise specified.
a
Data are given as number (percentage) of participants unless otherwise
indicated.
b
P .001.
c
P .02.
d
Excludes pairs with more than 1 member with “other ASD.”
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COMMENT
This study is the largest to date of proband-ascertained
twin pairs with at least 1 autistic proband (N=277); our
findings confirm the importance of genetic and nonge-
netic factors in contributing to ASDs and the validity of
a new Internet-based autism registry.
15-19,32,33
Our data also
suggest that zygosity and sex may contribute to ASD
heritability.
CONCORDANCE IN DZ
VS MZ TWINS
Concordance rates among DZ twins are consistent with
other studies, including the largest and most recent twin
study in Japan, which also reported an overall DZ con-
cordance rate of approximately 30%.
15,19
Other studies have
reported concordance rates among DZ twins as low as
0%, although the largest sample size was fewer than 60
pairs.
16-18
This moderately high concordance among DZ
twins, especially male-male pairs, also contrasts with pre-
viously reported rates of nontwin sibling occurrence of
ASD between 3% and 14%, and at least 20% if including
the broad autism phenotype.
4,12,15,19,27-29,34-38
This discrep-
ancy may be owing to selection bias for multiplex fami-
lies, which is inherent in voluntary registries such as IAN,
or for families with higher socioeconomic status
33,38
; lack
of stoppage rules for twins; or secular changes in diag-
nostic trends.
18,24,28
However, in our study, MZ concor-
dance for ASDs is consistent with earlier literature, which
reported rates of 80% to 100%, suggesting that our data
are reliable.
15-19
As expected, concordance of developmental mile-
stones and other natural history features, including ID,
within DZ twin pairs was lower than within MZ twin pairs.
In addition, DZ twins had significantly more discor-
dance for overall skill loss, and somewhat more for early
social skills loss, which is an intriguing finding because
autistic regression has emerged as a controversial topic
in clinical practice and research.
39
ROLE OF ZYGOSITY IN ASD PHENOTYPE
Apart from overall concordance, we found several un-
expected patterns relating ASD type with zygosity. Over-
all, affected DZ individuals had higher proportions of ID
and AD and significantly earlier age at onset than their
MZ counterparts (Table 1). The latter may be partly ow-
ing to a rater contrast effect or because DZ individuals
with ASDs display a different, more severe subtype of ASD
with obvious developmental delays, necessitating ear-
lier medical attention.
40
However, the proportion of DZ
individuals with AS is lower than the 10% to 15% esti-
mates for AS within ASDs. We did not control for age in
this population, but there was no significant difference
in mean age between twin types.
In addition, among concordant male-male twin pairs,
DZ twins were significantly less likely to be concordant
for AS than for AD or PDD-NOS and significantly more
likely to show severity discordance (Table 3). Our data
also support the theory that AS is inherited differently
than AD and PDD-NOS because concordant MZ twin pairs
are much less likely to have 1 twin with AS and 1 with
AD or PDD-NOS (Table 3). In addition, the high AS-AS
1.00
0.25
0.75
0.50
0 504020 3010
Lag Time Between Co-twin Diagnoses, mo
Disease-Free Survival
DZ
MZ
Figure 2. Lag in autism spectrum disorder diagnosis among concordant twin
pairs, dizygotic (DZ) (n=32) vs monozygotic (MZ) (n=29).
Table 3. ASD Concordance by Twin Type and Sex
No. of
Twin Pairs
Overall ASD
Concordance
Neither Twin
Had Undefined ASD,
No. of Twin Pairs
Diagnoses, % of Twin Pairs
P Value
(Fisher Exact Test)
AS for
Both
AD/PDD-NOS
for Both
AD/PDD-NOS
and AS
Affected and
Unaffected
MM vs
FX
MM MZ vs
MM DZ
MZ
MM 58 86.2 50 14.0 70.0 2.0 14.0
.30 .01FF 9 100 8 0.0 87.5 12.5 0.0
Total 67 88.1 58 . . . . . . . . . . . .
DZ
MM 97 40.2 82 2.2 26.8 8.5 62.5
.03 . . .
FF and FM 113 22.1 103 0.0 17.5 2.9 79.6
FF 23 26.1 21 0.0 19.1 4.8 76.2
FM 90 21.1 82 0.0 17.1 2.4 80.5
Total 210 30.5 185 . . . . . . . . . . . .
Abbreviations: AD, classic autism or autistic disorder; AS, Asperger syndrome; ASD, autism spectrum disorder; DZ, dizygotic; ellipses, not applicable;
FF, female-female; FM, female-male; FX, pairs with at least 1 female member; MM, male-male; MZ, monozygotic; PPD-NOS, pervasive developmental disorder, not
otherwise specified.
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concordance, along with higher proportions of normal
IQ and affective disorder among MZ vs DZ male-male
twins, suggests that AS phenotype is strongly influ-
enced by genes involved in selective aspects of social in-
teraction.
7,41
This is a particularly interesting finding given
speculation that environmental factors play a larger role
in the heritability of AS by affecting discrete social and
communication traits unlinked to functional ability
42
; our
data, with low discordance among MZ twins, suggest that
AS may be transmitted along different pathways than
AD and PDD-NOS. These puzzling data warrant further
examination.
In AD, which disproportionately affects males by about
4.3:1 (and perhaps twice as much in AS), the role of sex
is complex and important.
4,43
Because no consistent varia-
tion on the X chromosome has been found, there may
exist different propensities or even modalities for ex-
pression of ASDs in females vs males.
11,44
The 100% con-
cordance among female-female MZ twins compared with
86% concordance among male-male MZ twins, al-
though not statistically significant, and the lack of AS
among female-female MZ twins suggest that some other
factor may protect against full expression of the ASD phe-
notype in one member of male-male MZ twin pairs. How-
ever, our small sample size prohibits us from making a
more definite conclusion.
19,33
This sex variation also is evi-
dent in DZ concordance data, with significantly in-
creased risk of concordance among male-male DZ pairs
compared with female-female and female-male DZ pairs,
which perhaps suggests increased susceptibility for an
ASD diagnosis among males.
At the clinical level, several issues emerged from this
study. Of particular relevance to families and health care
providers, the longitudinal pattern seen in the Kaplan-
Meier survival curve of lag time in age at ASD diagnosis
among concordant twins (Figure 2) suggests that the early
months after a proband diagnosis are most important for
risk of co-twin ASD diagnosis. Also, a diagnosis of PDD
(not PDD-NOS) or ASD did not represent misdiagnosed
PDD-NOS and instead suggests that current DSM-IV-TR
criteria conflict with regional and evaluator variation.
Last, the rate of parent-reported ID (20%) among
our entire ASD twin population is much lower than in
other literature. This finding may reflect the true rate of
Table 4. Intrapair Discordance of Features Among 59 Concordant Twin Pairs
No. (%) Discordant/
Total No. of Pairs
2
DZ vs MZ
P Value
(Fisher Exact Test)
DZ Twins MZ Twins 1-Tailed 2-Tailed
Total No. of pairs 31 28
Age at first concern, before or after 18 mo 7 (23)/31 4 (14)/28 0.67 .32 .51
Development
Any lost skills
a
9 (33)/27 2 (8)/25 5.00 .03 .04
Specific lost skills
a
7 (26)/27 2 (8)/25 2.92 .09 .14
Approximate age at walking 11 (36)/31 5 (18)/28 2.31 .11 .15
Approximate age at talking 20 (65)/31 11 (39)/28 3.76 .05 .07
Approximate age at toilet training 15 (48)/31 9 (32)/28 1.61 .16 .29
Education
Has aide 11 (37)/30 7 (26)/27 0.76 .28 .38
Any special education 6 (19)/31 3 (11)/28 0.85 .29 .48
Comorbidities
Attention-deficit/hyperactivity disorder 6 (19)/31 2 (7)/28 1.87 .16 .26
Bipolar disorder 2 (7)/31 2 (7)/28 0.01 .65 1.0
Anxiety disorder 6 (19)/31 3 (11)/28 0.85 .29 .48
Seizure disorder 4 (13)/31 2 (7)/28 0.53 .39 .67
Intellectual disability 6 (19)/31 1 (4)/28 3.51 .07 .11
Abbreviations: DZ, dizygotic; MZ, monozygotic.
a
Refers to moderate to severe loss of social and/or communication skills before age 3 years.
Table 5. Autism Screening Discordance by Twin Type Among Concordant Pairs
Twin
Type
Social Responsiveness Scale
Social Communication Questionnaire
No. Completed/
Total Eligible
a
Mean t Score Difference
(95% Confidence Interval)
P Value
(t Test)
No. (%) of
Screenings Discordant,
by Severity Category
b
No. Completed/
Total Eligible
a
No. (%) of
Pairs Discordant
P Value
(
2
)
DZ 9/60 2.22 (−17.9 to 22.3) .81 3/9 (33.3) 36/64 9/36 (25.0)
.88
MZ 13/50 4.34 (−3.8 to 12.6) .27 5/13 (38.5) 30/59 5/30 (16.7)
DZ:MZ . . . 2.16 (−19.9 to 15.6) .80 . . . . . . . . . . . .
Abbreviations: DZ, dizygotic; MZ, monozygotic.
a
Completed for both twins; twins were eligible if both were concordant and met age criteria (see the “Social Responsiveness Scale” subsection in the
“Methods” section).
b
Categories based on t score: likely unaffected, 55; borderline, 55-59; mild to moderate, 60-75; severe, 75.
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ID diagnosis in the community and/or selection bias for
incomplete participation by families with 2 affected twins
with ID. Similar to our data on psychiatric comor-
bidites, mental retardation or ID status is most appro-
priately viewed as a comparison of status within a sib-
ship rather than as an absolute measure of those disorders
in the ASD population.
STUDY LIMITATIONS
The parent-reported, Web-based voluntary registry has
potential reliability limits. However, current research sup-
ports Web-based surveys on medical information as a re-
liable means of data collection.
45
This is also the experi-
ence of one of us (W.E.K.) with InterRett, the Rett
syndrome database based predominantly on parent-
reported data, which has led to several critical publica-
tions on this related neurodevelopmental disorder.
46
First,
in the design of the IAN Project, consenting families com-
plete detailed demographic information and are only per-
mitted one registration per household; the process in-
volves several steps, including confirmation of e-mail
address as well as informed consent to participate in IAN
Project research. Furthermore, the risk of fabricated di-
agnosis or self-diagnosis of ASDs is reduced via mul-
tiple detailed questions about ASD diagnosis.
Parent-reported data may also suffer from decreased
validity. For example, we cannot be certain that data about
zygosity are accurate; considering that parents err by mis-
classifying DZ twins as MZ twins,
47
the lower-than-
expected percentage of MZ twins in this study does not
support that bias.
45
For overall ASD status, most af-
fected individuals had positive results on the SCQ (95%)
and SRS (97%) (Table 1); we realize that the SCQ is
neither 100% sensitive nor specific. The IAN is cur-
rently analyzing data as part of a validity study, which
will help to allay these concerns.
Other threats to validity are secular trends in diagno-
sis, including trends over time and by location. In par-
ticular, although there is some concern that AS is not con-
sistently diagnosed at the community level (and is,
anecdotally, overdiagnosed), we believe that because of
diagnostic comparisons within twin pairs, the high rates
of positive SCQ results among all affected individuals,
and the distinct diagnostic differences between AS and
the other ASDs in terms of level of functioning, our find-
ings warrant further investigation.
Finally, although there are demographic and selec-
tion biases within the IAN population (eg, higher paren-
tal education level and lower minority enrollment), our
conclusions focus on intrapair variation and not com-
parisons with the general US or ASD populations, and
we assume that such biases are evenly distributed through-
out the IAN registry. Also, the IAN does not specifically
target families of twins nor is it geographically limited,
making these data less prone to these types of ascertain-
ment bias, although multiplex families may be more likely
to engage in IAN research.
33
Overall, these data have the
advantage of reflecting actual practice patterns rather than
the more strictly defined but less generalizable environ-
ment of clinical research laboratories.
CONCLUSIONS
This cross-sectional study includes the largest sample of
twins with at least 1 ASD-affected sibling, culled from a
US online autism registry. Further investigation of phe-
notypes, ASD in multiplex families, and more sophisti-
cated genetic modeling, especially focusing on sex as a risk
factor, would help in revealing potential nongenetic in-
fluences on concordance among different types of twins.
Because the genetic basis of this highly heritable
1
yet hetero-
geneous neuropsychiatric disorder is still not well under-
stood, further family and twin studies, including IAN data
on multiplex families, could help elucidate inheritance pat-
terns, phenotypes,
22-24
and, ultimately, genetic targets for
identification and treatment.
10,11,38
Accepted for Publication: February 12, 2009.
Correspondence: Paul A. Law, MD, MPH, Department
of Medical Informatics, Kennedy Krieger Institute, 3825
Greenspring Ave, Painter Bldg, 1st Floor, Baltimore, MD
21211 (lawp@kennedykrieger.org).
Author Contributions: Drs Rosenberg, P. A. Law, and
Kaufmann had full access to the data and take respon-
sibility for the integrity of the data and the accuracy of
the data analysis. Study concept and design: J. K. Law,
P. A. Law, and Kaufmann. Acquisition of data: J. K. Law
and P. A. Law. Analysis and interpretation of data: Rosen-
berg, J. K. Law, Yenokyan, McGready, and P. A. Law.
Drafting of the manuscript: Rosenberg. Critical revision of
the manuscript for important intellectual content: Rosen-
berg, J. K. Law, Yenokyan, McGready, P. A. Law, and Kauf-
mann. Statistical analysis: Rosenberg, Yenokyan, and
McGready. Obtained funding: J. K. Law and P. A. Law. Ad-
ministrative, technical, and material support: Rosenberg.
Study supervision: J. K. Law, P. A. Law, and Kaufmann.
Financial Disclosure: None reported.
Funding/Support: This study was supported by Autism
Speaks.
Disclaimer: The opinions expressed herein are those of
the authors and do not necessarily reflect the views of
Autism Speaks. The funder had no input regarding study
design or conduct, data analysis or interpretation, manu-
script preparation, or the decision to submit the results
for publication.
Additional Contributions: John Constantino, MD, and
Connie Anderson, PhD, provided helpful comments. We
especially thank the many families who are part of the
IAN for sharing their few spare moments.
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I’m bored with that line. I never use it any-
more. My new line is, “In 15 minutes, every-
body will be famous.”
—Andy Warhol
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    • "Studies have shown that among identical twins, if one child has ASD, then the other has a 36–95 % chance of also having the disease. In non-identical twins, if one twin has ASD, then the probability of the other twin having ASD is between 0 and 31 % (Rosenberg et al. 2009; Hallmayer et al. 2011; Ronald et al. 2006). The most effective therapeutic intervention currently available for ASD is early behavioral therapy. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Autism spectrum disorders (ASD) is a group of neurodevelopmental disorders believed to have a multifactorial basis. Presently, diagnosis is based on behavioral and developmental signs in children before the age of 3 and no reliable clinical biomarkers are available for early detection. Objectives This study aimed to biochemically profile the cerebellum from post-mortem human brain from ASD sufferers (n = 11) and compare their profiles to that of age-matched controls (n = 11) with no known brain disorder. Methods Using liquid chromatography combined with LTQ-Orbitrap mass spectrometry we detected 14,328 features in ESI+ mode in polar extracts of post-mortem brain. Results Of these only 37 were found to be statistically significantly different between ASD and controls (p < 0.05; fdr < 0.05). A panel of four features had a predictive power of 96.64 %, following statistical cross validation, for ASD detection. This model produced an AUC = 0.874 (CI 0.768–0.944) and a Fisher’s exact score of p = 4.50E−29. Conclusion Whilst at this time we were unable to chemically identify the four features of interest we believe that this study underscores the potential value of high resolution metabolomics for the study of ASD. Further characterization of the polar metabolome of post mortem ASD brains could lead to the identification of potential biomarkers and novel therapeutics for the disease. The development of accurate biomarkers could assist in the early detection of ASD and promote early intervention strategies to improve outcome.
    No preview · Article · Apr 2016 · Metabolomics
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    • "Quantitative measures of heritability are derived from rates of concordance for monozygotic twins, dizygotic twins, and siblings, with some evidence coming from a 2014 survey of more than two million Swedish families, the largest population-based study of ASD so far (Sandin et al., 2014 ). With one notable exception (Hallmayer et al., 2011), heritability estimates range from 52%–90% (Chen et al., 2015; Buxbaum, 2015a, 2015b; Gaugler et al., 2014; Rosenberg et al., 2009; Sandin et al., 2014; Toro et al., 2010). Thus, genetic factors contribute substantially and likely combine with environmental effects to guide clinical outcome (Bourgeron, 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.
    Preview · Article · Mar 2016 · Neuron
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    • "These findings were likely due to the difficulty of the task used in this study, based on prior findings that failed to show a Cntnap2 deficit when compared to WTs on a simple MWM learning task [18]. Current findings are consistent with deficits in executive learning as demonstrated in ASD [17,22,23,10]. Moreover, our findings may further explain the dyad of core symptoms, given the central role of executive processing in both higher and lower levels of processing. "
    [Show abstract] [Hide abstract] ABSTRACT: Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with core symptoms of atypical social interactions and repetitive behaviors. It has also been reported that individuals with ASD have difficulty with multisensory integration, and this may disrupt higher-order cognitive abilities such as learning and social communication. Impairments in the integration of sensory information could in turn reflect diminished cross-modal white matter connectivity. Moreover, the genetic contribution in ASD appears to be strong, with heritability estimates as high as 90%. However, no single gene has been identified, and over 1000 risk genes have been reported. One of these genes – contactin-associated-like-protein 2 (CNTNAP2) – was first associated with Specific Language Impairment, and more recently has been linked to ASD. CNTNAP2 encodes a cell adhesion protein regulating synaptic signal transmission. To better understand the behavioral and biological underlying mechanisms of ASD, a transgenic mouse model was created with a genetic knockout (KO) of the rodent homolog Cntnap2. Initial studies on this mouse revealed poor social interactions, behavioral perseveration, and reduced vocalizations—all strongly resembling human ASD symptoms. Cntnap2 KO mice also show abnormalities in myelin formation, consistent with a hypo-connectivity model of ASD. The current study was designed to further assess the behavioral phenotype of this mouse model, with a focus on learning and memory. Cntnap2 KO and wild-type mice were tested on a 4/8 radial arm water maze for 14 consecutive days. Error scores (total, working memory, reference memory, initial and repeated reference memory), latency and average turn angle were independently assessed using a 2 × 14 repeated measures ANOVA. Results showed that Cntnap2 KO mice exhibited significant deficits in working and reference memory during the acquisition period of the task. During the retention period (i.e., after asymptote in errors), Cntnap2 KO mice performed comparably to wild-type mice. These findings suggest that CNTNAP2 may influence the development of neural systems important to learning and cross-modal integration, and that disruption of this function could be associated with delayed learning in ASD.
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