European Child & Adolescent Psychiatry

https://doi.org/10.1007/s00787-021-01784-9

ORIGINAL CONTRIBUTION

Developmental and mental health risks among siblings of patients

with autism spectrum disorder: a nationwide study
Hung‑Chen Lin1,2,5 · Chih‑Ming Cheng1,2,5 · Kai‑Lin Huang1,2,5 · Ju‑Wei Hsu1,2,5 · Ya‑Mei Bai1,2,5 · Shih‑Jen Tsai1,2,5 ·
Tzeng‑Ji Chen3,4,5 · Mu‑Hong Chen1,2,5

Received: 24 April 2020 / Accepted: 11 April 2021

© Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Studies have suggested that unaffected siblings of patients with autism spectrum disorder (ASD) have some other neurode-
velopmental abnormalities. However, the risks of mental and developmental disorders have rarely been investigated among
unaffected siblings. Using Taiwan’s National Health Insurance Research Database, 1304 unaffected siblings born between
1980 and 2010 with ASD probands and 13,040 age-/sex-/family structure-matched controls were included in our study
and followed up from 1996 or birth to the end of 2011. Developmental delay, language delay, developmental coordina-
tion disorder, attention-deficit hyperactivity disorder (ADHD), anxiety disorders, disruptive behavior disorders, unipolar
disorder, and bipolar disorder were identified during the follow-up period. Unaffected siblings were more likely to develop
any developmental delay, developmental speech or language disorder, developmental coordination disorder, intelligence
disability, ADHD, anxiety disorders, unipolar depression, and disruptive behavior disorders compared with the control
group. Brothers of patients with ASD had a higher risk of neurodevelopmental abnormalities, ADHD, anxiety disorders, and
disruptive behavior disorders; sisters were prone to having neurodevelopmental abnormalities, ADHD, anxiety disorders,
unipolar depression, and disruptive behavior disorders. Unaffected siblings of patients with ASD were prone to developing
any developmental or mental disorder later in life. Clinicians and public health officials should pay more attention to the
developmental condition and mental health of unaffected siblings of patients with ASD.

Keywords Siblings · Autism spectrum disorder · Developmental delay · Attention-deficit hyperactivity disorder · Mental
disorders

Autism spectrum disorder (ASD), one of the commonest

neurodevelopmental disorders, begins in childhood and
Hung-Chen Lin and Chih-Ming Cheng contributed equally to this is characterized by deficits in communication and social
work.
interaction across multiple contexts and restricted, repeti-
* Ju‑Wei Hsu tive patterns of behavior, interests, and activities [1]. ASD
jwhsu@vghtpe.gov.tw is highly prevalent in Europe, Asia, and the United States,
* Mu‑Hong Chen with prevalence ranging from 2 to 25 per 1000 persons, or
kermer7119@gmail.com approximately 1 in 40 to 1 in 500 persons, with a male-to-
female ratio in the range of 3:1 to 4:1 [1–3]. Multiple genetic
1
Department of Psychiatry, Taipei Veterans General Hospital, and environmental factors result in a spectrum of neurobio-
No. 201, Shih‑Pai Road, Sec. 2, 11217 Taipei, Taiwan
logical vulnerabilities in people with ASD.
2
Division of Psychiatry, School of Medicine, National Yang A growing body of evidence has reported that unaffected
Ming Chiao Tung University, Taipei, Taiwan
siblings of patients with ASD may exhibit the broad ASD
3
Department of Family Medicine, Taipei Veterans General phenotype and have other neurodevelopmental abnormali-
Hospital, Taipei, Taiwan
ties, including developmental speech or language disorder,
4
Institute of Hospital and Health Care Administration, developmental coordination disorder, and intelligence dis-
National Yang Ming Chiao Tung University, Taipei, Taiwan
ability, even though they do not meet the criteria for an ASD
5
Department of Psychiatry, General Cheng Hsin Hospital, diagnosis [4–12]. Yirmiya et al. compared the cognitive and
Taipei, Taiwan

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language skills of 30 siblings of children with autism and 30
siblings of typically developing children [11]. Nonsignifi-
cant group differences emerged related to cognition at 24
and 36 months, but siblings of children with autism differed
significantly in terms of language difficulties. The study of
Gamliel et al. demonstrated that 40% of siblings of patients
with autism at age of 7 years manifested cognitive, language,
or learning difficulties, as measured by parental reports and
standardized test scores [5]. Cognitive development delay
may have disappeared at age 54 months, but some language
ability differences remained [6]. Furthermore, the comor-
bidities of ASD with attention-deficit hyperactivity disorder
(ADHD), unipolar and bipolar disorders, anxiety disorders,
and disruptive behavior disorders have been commonly
reported in related studies [13–16]. However, the preva-
lence of the aforementioned psychiatric disorders has rarely
been investigated among unaffected siblings of patients with
ASD [17]. Furthermore, researchers have yet to reach a con-
sensus on the depressive symptoms of siblings of patients
with ASD; some studies have demonstrated a significantly
higher risk of depression [15, 18] and others have shown no
differences in depressive symptoms between siblings and
comparison groups [19]. The association between unaffected
siblings of probands with ASD and aforementioned psychi-
atric disorders requires confirmation.
This study used the Taiwan National Health Insurance
Research Database (NHIRD), a large sample size, and a lon-
gitudinal follow-up design to investigate the developmental
and mental disorders among unaffected siblings of patients
with ASD. We hypothesized that the unaffected siblings of
such patients are more likely to have developmental prob-
lems or develop other mental disorders, such as affective
disorders, ADHD, and disruptive behavior disorders, during
the follow-up period compared with the control group.
Methods
Data source
Taiwan National Health Insurance Research Database
(NHIRD) which consists of healthcare data from > 99%
of the entire Taiwan population is audited and released by
National Health Research Institute for scientific and study
purposes. Comprehensive information on insured individu-
als is included in the database, including demographic data,
dates of clinical visits, disease diagnoses, and medical inter-
ventions. Individual medical records included in the NHIRD
are anonymous to protect patient privacy. Subsequently,
following the method of Kuo et al. family kinships in the
NHIRD were used for genealogy reconstruction [20]. The
diagnostic codes used were based on the International Clas-
sification of Diseases, 9th Revision, Clinical Modification
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European Child & Adolescent Psychiatry
(ICD-9-CM). The NHIRD has been used extensively in
many epidemiologic studies in Taiwan [21–24]. With the
formal application, only data between 1996 and 2011 were
required in our study team.
Inclusion criteria for the unaffected siblings of ASD
probands and the control group
Individuals who were born between 1980 and 2010 and had
no diagnosis of ASD (ICD-9-CM code: 299) at any time
but had any sibling with ASD were enrolled as the ASD
sibling cohort. The age-, sex-, birth year-, and family struc-
ture-matched (1:10) control cohort was randomly identi-
fied after eliminating those who had been given a diagnosis
of ASD at any time and those with any sibling with ASD.
Family structure was based on the sibling numbers and was
matched to reduce the identification bias within a family.
ASD sibling cohort and control cohort were followed from
1996 or the birth year to the end of 2011 for the investiga-
tion of occurrence of developmental and mental health risks.
Developmental disorders included any developmental delay,
developmental speech or language disorder, developmen-
tal coordination disorder, and intelligence disability. Men-
tal disorders included ADHD, anxiety disorders, unipolar
depressive disorder, bipolar disorder, and disruptive behav-
ior disorders. Mental disorders were diagnosed by board-
certified psychiatrists, and developmental disorders were
diagnosed by board-certified psychiatrists, pediatricians,
and rehabilitation medicine physicians. Level of urbaniza-
tion (level 1 to level 5; level 1: most urbanized region; level
5: least urbanized region) was also assessed for our study
[25]. This study was approved by the Institutional Review
Board of Taipei Veterans General Hospital.
Statistical analysis
For between-group comparisons, the F test was used for
continuous variables and Pearson’s X2 test for nominal vari-
ables, where appropriate. To manage the effects of cluster-
ing, conditional logistic regressions with the adjustment of
demographic data (age, sex, and level of urbanization) were
performed to calculate the odds ratios (OR) and 95% con-
fidence interval (95% CI) of developing developmental and
mental disorders between our matched ASD sibling cohort-
control cohort. Additional conditional logistic regression
analyses stratified by sex were also examined to investigate
the role of sex in the risks of subsequent developmental and
mental disorders. A two-tailed p value of less than 0.05 was
considered statistically significant. All data processing and
statistical analyses were performed with Statistical Package
for Social Science (SPSS) version 17 software (SPSS Inc.)
and Statistical Analysis Software (SAS) version 9.1 (SAS
Institute, Cary, NC).
European Child & Adolescent Psychiatry

Results
In all, 1304 unaffected siblings of patients with ASD and
13,040 age-/sex-/family structure-matched controls were
included in our study. ASD sibling cohort had a higher
prevalence of any developmental delay (11.9% vs. 3.6%,
p < 0.001), developmental speech or language disorder
(6.2% vs. 2.2%, p < 0.001), developmental coordination
disorder (1.8% vs. 0.5%, p < 0.001), and intelligence dis-
ability (3.0% vs. 1.1%, p < 0.001) than the controls did
(Table 1). During the follow-up period, ASD sibling
cohort had a higher prevalence of ADHD (7.8% vs. 2.3%,
p < 0.001), anxiety disorders (4.4% vs. 1.3%, p < 0.001),
unipolar depression (1.6% vs. 0.8%, p = 0.004), and dis-
ruptive behavior disorders (1.1% vs. 0.2%, p < 0.001)
compared with the controls (Table 1). The ASD sibling
cohort resided more in urbanized region (p < 0.001).
Conditional logistic regression analyses with the
adjustment of age, sex, and level urbanization showed
that the unaffected siblings of patients with ASD were
more likely to have any developmental delay (OR: 3.71,
95% CI: 3.05–4.52), developmental speech or language
disorder (OR: 2.98, 95% CI: 2.31–3.86), developmental
coordination disorder (OR: 3.45, 95% CI: 2.14–5.58),
and intelligence disability (OR: 2.96, 95% CI: 2.06–4.25)
compared with the control group (Table 2). Stratified
by sex, brothers of patients with ASD had an increased
risk of developing any developmental delay (OR: 2.84,
95% CI: 2.17–3.71), developmental speech or language
disorder (OR: 2.07, 95% CI: 1.44–2.97), developmental
coordination disorder(OR: 2.85, 95% CI: 1.44–5.63), and
intelligence disability (OR: 2.63, 95% CI: 1.65–4.20);

Table 1  Demographic data and Siblings of ASD Controls p value

prevalence of the developmental probands (n = 13,040)
and mental disorders among (n = 1304)
siblings of ASD probands and
controls Age in 2010 (years, SD) 14.90 (7.20) 14.93 (7.20) 0.894
Sex (n, %) 1.000
Male 591 (45.3) 5910 (45.3)
Female 713 (54.7) 7130 (54.7)
Prevalence of developmental disorders
Any developmental delay (n, %) 155 (11.9) 473 (3.6) < 0.001
Age at diagnosis (years, SD) 4.40 (2.89) 4.34 (2.78) 0.815
Developmental speech or language disorder (n, %) 81 (6.2) 291 (2.2) < 0.001
Age at diagnosis (years, SD) 3.99 (2.23) 4.16 (2.59) 0.366
Developmental coordination disorder (n, %) 23 (1.8) 67 (0.5) < 0.001
Age at diagnosis (years, SD) 5.40 (2.84) 4.95 (1.75) 0.590
Intelligence disability (n, %) 39 (3.0) 138 (1.1) < 0.001
Age at diagnosis (years, SD) 8.66 (4.33) 9.52 (5.16) 0.346
Prevalence of mental disorders
ADHD (n, %) 102 (7.8) 302 (2.3) < 0.001
Age at diagnosis (years, SD) 7.74 (2.74) 8.02 (2.49) 0.351
Anxiety disorders (n, %) 57 (4.4) 163 (1.3) < 0.001
Age at diagnosis (years, SD) 13.49 (5.88) 14.97 (6.30) 0.124
Depressive disorders (n, %) 21 (1.6) 102 (0.8) 0.004
Age at diagnosis (years, SD) 17.71 (4.42) 19.09 (3.94) 0.365
Bipolar disorders (n, %) 2 (0.2) 17 (0.1) 0.689
Age at diagnosis (years, SD) 16.00 (7.07) 19.55 (4.81) 0.465
Disruptive behavior disorder (n, %) 14 (1.1) 32 (0.2) < 0.001
Age at diagnosis (years, SD) 11.33 (3.44) 10.40 (3.90) 0.447
Level of urbanization (n, %) < 0.001
1 (most urbanized) 279 (21.4) 2116 (16.2)
2 408 (31.3) 3911 (30.0)
3 103 (7.9) 1510 (11.6)
4 91 (7.0) 1301 (10.0)
5 (most rural) 423 (32.4) 4202 (32.2)

ASD autism spectrum disorder; ADHD attention-deficit hyperactivity disorder; SD standard deviation

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Table 2  Conditional logistic regression analyses of the developmental disorders among siblings of ASD probands and controls*
Developmental disorders
Any developmental delay Developmental speech or Developmental coordination Intelligence disability
(OR, 95% CI) language disorder disorder (OR, 95% CI) (OR, 95% CI)
(OR, 95% CI)

Siblings of ASD probands 3.71 (3.05–4.52) 2.98 (2.31–3.86) 3.45 (2.14–5.58) 2.96 (2.06–4.25)
Brothers of ASD probands 2.84 (2.17–3.71) 2.07 (1.44–2.97) 2.85 (1.44–5.63) 2.63 (1.65–4.20)
Sisters of ASD probands 5.27 (3.94–7.04) 4.85 (3.33–7.08) 4.19 (2.12–8.30) 3.60 (2.03–6.41)

ASD autism spectrum disorder; OR odds ratio; CI confidence interval

Bold type means the statistical significance
*
Adjusted for demographic data

sisters of patients with ASD were prone to having any Discussion

developmental delay (OR: 5.27, 95% CI: 3.94–7.04),
developmental speech or language disorder (OR: 4.85,
95% CI: 3.33–7.08), developmental coordination disorder
(OR: 4.19, 95% CI: 2.12–8.30), and intelligence disability
(OR: 3.60, 95% CI: 2.03–6.41) compared with the con-
trols (Table 2).
In addition, the ASD sibling cohort were more likely
to develop ADHD (OR: 3.64, 95% CI: 2.87–4.60), anxi-
ety disorders (OR: 3.65, 95% CI: 2.68–4.99), unipolar
depression (OR: 2.10, 95% CI: 1.30–3.41), and disrup-
tive behavior disorders (OR: 4.37, 95% CI: 2.32–8.23)
compared with the control group (Table 3). Stratified by
sex, brothers of patients with ASD had an increased risk
of subsequent ADHD (OR: 3.07, 95% CI: 2.29–4.10),
anxiety disorders (OR: 3.17, 95% CI: 2.04–4.94),
and disruptive behavior disorders (OR: 3.49, 95% CI:
1.55–7.87) compared with the controls; sisters of patients
with ASD were prone to developing ADHD (OR: 5.22,
95% CI: 3.48–7.84), anxiety disorders (OR: 4.27, 95%
CI: 2.75–6.62), unipolar depression (OR: 2.23, 95%
CI: 1.20–4.14) and disruptive behavior disorders (OR:
6.57, 95% CI: 2.32–18.59) compared with the controls
(Table 3).
Our study findings supported the study hypothesis that unaf-
fected siblings of patients with ASD were more likely to
exhibit symptoms of developmental delay, such as those
related to intellectual disability, language delay, and devel-
opmental coordination disorder and to develop ADHD, anxi-
ety disorders, disruptive behavior disorders, and unipolar
depression compared with controls. Both brothers and sisters
of patients with ASD had similar risks of developing devel-
opmental and mental disorders during the follow-up period.
As mentioned, the broad ASD phenotype or associated
neurodevelopmental abnormalities commonly occurred in
the unaffected siblings of patients with ASD [7–10, 12].
Yirmiya et al. compared the cognitive and language skills of
30 siblings of children with ASD and 30 siblings of typically
developing children and demonstrated that nonsignificant
group differences emerged for cognition at 24 and 36 months
and that the groups differed significantly in terms of lan-
guage difficulties [11]. Gamliel et al. further reported that
40% of siblings of children with ASD, compared with 16%
of siblings of typically developing children, were identified
as manifesting cognitive, language, and learning difficul-
ties at age 7 years [5]. Miller et al. compared estimates of
recurrence risk in later-born siblings of children with ASD

Table 3  Conditional logistic regression analyses of the mental disorders among siblings of ASD probands and controls*
Mental disorders
ADHD Anxiety disorders Depressive disorders Bipolar disorders Disruptive behavior disorder
(OR, 95% CI) (OR, 95% CI) (OR, 95% CI) (OR, 95% CI) (OR, 95% CI)

Siblings of ASD probands 3.64 (2.87–4.60) 3.65 (2.68–4.99) 2.10 (1.30–3.41) 1.17 (0.27–5.11) 4.37 (2.32–8.23)
Brothers of ASD probands 3.07 (2.29–4.10) 3.17 (2.04–4.94) 1.96 (0.900–4.24) 1.37 (0.17–11.28) 3.49 (1.55–7.87)
Sisters of ASD probands 5.22 (3.48–7.84) 4.27 (2.75–6.62) 2.23 (1.20–4.14) 1.02 (0.13–8.04) 6.57 (2.32–18.59)

ASD autism spectrum disorder; ADHD attention-deficit hyperactivity disorder; OR odds ratio; CI confidence interval
Bold type means the statistical significance
*
Adjusted for demographic data

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with those of later-born siblings of children without ASD
and revealed that later-born siblings of children with ASD
were more likely to receive a diagnosis of ASD and ADHD
[26]. In their study, Jokiranta-Olkoniemi et al. included 3578
patients with ASD with 6022 siblings and 11,775 controls
with 22,127 siblings from Finnish national registers and
demonstrated that siblings of patients with ASD had a higher
prevalence of ADHD, intellectual disability, childhood
emotional disorders, learning and coordination disorders,
conduct and oppositional disorders, anxiety disorders, and
affective disorders than their control counterparts [14]. A
growing body of evidence suggests that the effect of shared
genetic and environmental factors (i.e., interfamilial stress)
on the association between ASD and other developmental
and mental disorders, including language delay, ADHD, and
affective disorders, may be the reason behind such results
[26–30].
We demonstrated that brothers and sisters of patients with
ASD had similar risks of developmental disorders, ADHD,
anxiety disorders, and disruptive behavior disorders. In addi-
tion, we also found sisters but not brothers of patients with
ASD had an increased risk of developing depressive disorder
during the follow-up period. In the literature, most studies
have supported the hypothesis that siblings of ASD probands
have a higher likelihood of experiencing depression and anx-
iety [15, 16]; however, only a few studies have discussed
this in the differences between the sexes. For example, Nasr
Esfahani et al. in Iran investigated 30 cases and 30 controls
and reported that the depression was more severe in sisters
of siblings with ASD than in brothers of such siblings [31].
Orsmond and Seltzer in USA reported the same result in
teenage girls of siblings with ASD in similar sample size
[32]. Using NHIRD database, we confirmed the previous
finding in the larger and more comprehensive national-wide
sample, indicating that the susceptibility of depression for
sisters of ASD probands may be generalized in different
cultures.
In addition, we identified no increased risk of bipolar dis-
order in unaffected siblings of patients with ASD although
related studies have suggested a relationship between ASD
and bipolar disorder [33, 34]. In this study, we only enrolled
siblings born between 1980 and 2010 and followed them
up from 1996 to the end of 2011. The limited follow-up
duration may partially explain the nonsignificant association
between bipolar disorder risk and siblings of patients with
ASD. Additional studies with longer follow-up periods may
be necessary to clarify the risk of bipolar disorder among
siblings of patients with ASD.
Several study limitations were observed. First, the
prevalence of developmental and mental disorders may
have been underestimated because only those who sought
medical consultation and help would have been included
in the database. However, the diagnoses of developmental
and mental disorders were provided by board-certified
psychiatrists and physicians, thus improving diagnostic
validity. Second, unaffected siblings of patients with ASD
were enrolled in our study. However, additional clinical
studies are required to investigate whether those partici-
pants may have exhibited subthreshold ASD symptoms or
have ASD traits without being diagnosed as having ASD.
Third, the age of ASD diagnosis was not assessed among
ASD probands in current study, which may confound the
time when his or her siblings sought for developmental
and mental evaluation. In addition, the parental sensitiv-
ity to mental and developmental symptoms toward other
children may be related to the fact that they have raised
an ASD child. Whether the time of ASD diagnosis among
ASD probands and whether the parental sensitivity to
mental and developmental symptoms may be related to the
incidence of mental and developmental disorders among
unaffected siblings of ASD probands would be further
examined. Fourth, information, such as that related to
psychosocial stress, interfamilial stress, parental function-
ing, personal lifestyles, and environmental factors were
not available in NHIRD; therefore, we were unable to
investigate their potential influence. Fifth, the prenatal and
perinatal risk factors were not assessed in current study.
Whether unaffected siblings with ASD probands may be
more exposed to prenatal and perinatal risk factors would
need further investigation.
In conclusion, the unaffected siblings of patients with
ASD were more likely to develop any developmental delay,
language delay, developmental coordination disorder,
ADHD, anxiety disorders, disruptive behavior disorders,
and unipolar disorder later in life compared with the control
group. The confirmation of the underlying mechanisms of
the coaggregation of ASD with other developmental and
mental disorders requires further investigation. Our findings
may remind parents, clinicians, and public health officers
to closely monitor the developmental condition and mental
health of siblings of patients with ASD. Early identifica-
tion and assessment may be necessary for this high-risk
population.
Acknowledgement We thank Mr I-Fan Hu for his friendship and
support.
Funding The study was supported by grant from Taipei Veterans Gen-
eral Hospital (V105A-049, V106B-020, V107B-010, V107C-181)
and Ministry of Science and Technology, Taiwan (107–2314-B-075–
063-MY3, 108–2314-B-075 -037). The funding source had no role in
any process of our study.
Declarations
Conflict of interest All the authors declare no conflict of interest. All
the authors have no financial relationships relevant to this article to
disclose.
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References 20. Kuo CF, Grainge MJ, Valdes AM, See LC, Luo SF, Yu KH et al
(2015) Familial aggregation of systemic lupus erythematosus and
coaggregation of autoimmune diseases in affected families. JAMA
1. Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet
Intern Med 175(9):1518–1526
383(9920):896–910
21. Chen MH, Hsu JW, Huang KL, Bai YM, Ko NY, Su TP et al (2018)
2. Baio J, Wiggins L, Christensen DL, Maenner MJ, Daniels J, War-
Sexually transmitted infection among adolescents and young adults
ren Z et al (2018) Prevalence of autism spectrum disorder among
with attention-deficit/hyperactivity disorder: a nationwide longitu-
children aged 8 years—autism and developmental disabilities moni-
dinal study. J Am Acad Child Adolesc Psychiatry 57(1):48–53
toring network, 11 sites, United States, 2014. Morbid Mortal Week
22. Chen MH, Lan WH, Hsu JW, Huang KL, Su TP, Li CT et al (2016)
Report Surveill Summar (Washington, DC: 2002) 67(6):1–23
Risk of developing type 2 diabetes in adolescents and young adults
3. Loomes R, Hull L, Mandy WPL (2017) What is the male-to-female
with autism spectrum disorder: a nationwide longitudinal study.
ratio in autism spectrum disorder? A systematic review and meta-
Diabetes Care 39(5):788–793
analysis. J Am Acad Child Adolesc Psychiatry 56(6):466–474
23. Chen MH, Pan TL, Li CT, Lin WC, Chen YS, Lee YC et al (2015)
4. Dalton KM, Nacewicz BM, Alexander AL, Davidson RJ (2007)
Risk of stroke among patients with post-traumatic stress disor-
Gaze-fixation, brain activation, and amygdala volume in unaffected
der: nationwide longitudinal study. Brit J Psychiatry J Mental Sci
siblings of individuals with autism. Biol Psychiatry 61(4):512–520
206(4):302–307
5. Gamliel I, Yirmiya N, Jaffe DH, Manor O, Sigman M (2009) Devel-
24. Cheng CM, Chang WH, Chen MH, Tsai CF, Su TP, Li CT et al
opmental trajectories in siblings of children with autism: cogni-
(2018) Co-aggregation of major psychiatric disorders in individuals
tion and language from 4 months to 7 years. J Autism Dev Disord
with first-degree relatives with schizophrenia: a nationwide popula-
39(8):1131–1144
tion-based study. Mol Psychiatry 23(8):1756–1763
6. Gamliel I, Yirmiya N, Sigman M (2007) The development of young
25. Liu CY, Hung YT, Chuang YL, Chen YJ, Weng WS, Liu JS (2006)
siblings of children with autism from 4 to 54 months. J Autism Dev
Incorporating development stratification of Taiwan townships into
Disord 37(1):171–183
sampling design of large scale health interview survey. J Health
7. Lauritsen MB, Pedersen CB, Mortensen PB (2005) Effects of famil-
Manage (Chin) 4:1–22
ial risk factors and place of birth on the risk of autism: a nation-
26. Miller M, Musser ED, Young GS, Olson B, Steiner RD, Nigg JT
wide register-based study. J Child Psychol Psychiatry Allied Discip
(2019) Sibling recurrence risk and cross-aggregation of attention-
46(9):963–971
deficit/hyperactivity disorder and autism spectrum disorder. JAMA
8. Pisula E, Ziegart-Sadowska K (2015) Broader autism pheno-
Pediatr 173(2):147–152
type in siblings of children with ASD—a review. Int J Mol Sci
27. Ghirardi L, Brikell I, Kuja-Halkola R, Freitag CM, Franke B, Asher-
16(6):13217–13258
son P et al (2018) The familial co-aggregation of ASD and ADHD:
9. Piven J, Palmer P, Jacobi D, Childress D, Arndt S (1997) Broader
a register-based cohort study. Mol Psychiatry 23(2):257–262
autism phenotype: evidence from a family history study of multiple-
28. Musser ED, Hawkey E, Kachan-Liu SS, Lees P, Roullet JB, Goddard
incidence autism families. Am J Psychiatry 154(2):185–190
K et al (2014) Shared familial transmission of autism spectrum and
10. Tsai HJ, Cebula K, Fletcher-Watson S (2017) The role of the broader
attention-deficit/hyperactivity disorders. J Child Psychol Psychiatry
autism phenotype and environmental stressors in the adjustment of
Allied Discipl 55(7):819–827
siblings of children with autism spectrum disorders in Taiwan and
29. Septier M, Peyre H, Amsellem F, Beggiato A, Maruani A, Poumey-
the United Kingdom. J Autism Dev Disord 47(8):2363–2377
reau M et al (2019) Increased risk of ADHD in families with ASD.
11. Yirmiya N, Gamliel I, Shaked M, Sigman M (2007) Cognitive and
Eur Child Adolesc Psychiatry 28(2):281–288
verbal abilities of 24- to 36-month-old siblings of children with
30. Stergiakouli E, Davey Smith G, Martin J, Skuse DH, Viechtbauer
autism. J Autism Dev Disord 37(2):218–229
W, Ring SM et al (2017) Shared genetic influences between dimen-
12. Ruzich E, Allison C, Smith P, Watson P, Auyeung B, Ring H et al
sional ASD and ADHD symptoms during child and adolescent
(2016) Subgrouping siblings of people with autism: Identifying the
development. Mol Autism 8:18
broader autism phenotype. Autism Res 9(6):658–665
31. Nasr Esfahani F, Hakim Shooshtari M, Shirmohammadi Sosfadi R,
13. Gronborg TK, Schendel DE, Parner ET (2013) Recurrence of autism
Saeed F, Jalai F, Farsham A et al (2018) Internalizing and external-
spectrum disorders in full- and half-siblings and trends over time: a
izing problems, empathy quotient, and systemizing quotient in 4
population-based cohort study. JAMA Pediatr 167(10):947–953
to 11 years-old siblings of children with autistic spectrum disorder
14. Jokiranta-Olkoniemi E, Cheslack-Postava K, Sucksdorff D,
compared to control group. Iran J Psychiatry 13(3):191–199
Suominen A, Gyllenberg D, Chudal R et al (2016) Risk of psychi-
32. Orsmond GI, Seltzer MM (2009) Adolescent siblings of individuals
atric and neurodevelopmental disorders among siblings of probands
with an autism spectrum disorder: testing a diathesis-stress model
with autism spectrum disorders. JAMA Psychiat 73(6):622–629
of sibling well-being. J Autism Dev Disord 39(7):1053–1065
15. Lovell B, Wetherell MA (2016) The psychophysiological impact of
33. Schalbroeck R, Termorshuizen F, Visser E, van Amelsvoort T,
childhood autism spectrum disorder on siblings. Res Dev Disabilit
Selten JP (2019) Risk of non-affective psychotic disorder or bipolar
49–50:226–234
disorder in autism spectrum disorder: a longitudinal register-based
16. Quintero N, McIntyre LL (2010) Sibling adjustment and maternal
study in the Netherlands. Psychol Med 49(15):2543–2550
well-being: an examination of families with and without a child
34. Skokauskas N, Frodl T (2015) Overlap between autism spec-
with an autism spectrum disorder. Focus Autism Other Dev Disabil
trum disorder and bipolar affective disorder. Psychopathology
25(1):37–46
48(4):209–216
17. Piven J, Gayle J, Chase GA, Fink B, Landa R, Wzorek MM et al
(1990) A family history study of neuropsychiatric disorders in the
adult siblings of autistic individuals. J Am Acad Child Adolesc Psy-
chiatry 29(2):177–183
18. Hodapp RM, Urbano RC (2007) Adult siblings of individuals with
Down syndrome versus with autism: findings from a large-scale US
survey. J Intell Disabil Res JIDR 51(Pt 12):1018–1029
19. O’Neill LP, Murray LE (2016) Anxiety and depression symptoma-
tology in adult siblings of individuals with different developmental
disability diagnoses. Res Dev Disabil 51–52:116–125

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