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Table 1.  
Characteristics of the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
Characteristics of the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
Table 2.  
Associations Between ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
Associations Between ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
Table 3.  
Associations Between ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases With or Without ID and Siblings of Matched Controls in the Nationwide FIPS-A Studya
Associations Between ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases With or Without ID and Siblings of Matched Controls in the Nationwide FIPS-A Studya
Table 4.  
Associations Between Subgroups of ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
Associations Between Subgroups of ASD and Psychiatric and Neurodevelopmental Disorders Among the Siblings of Cases and Matched Controls in the Nationwide FIPS-A Studya
1.
World Health Organization.  International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Geneva, Switzerland: World Health Organization; 1992.
2.
Colvert  E, Tick  B, McEwen  F,  et al.  Heritability of autism spectrum disorder in a UK population-based twin sample.  JAMA Psychiatry. 2015;72(5):415-423.PubMedArticle
3.
Nordenbæk  C, Jørgensen  M, Kyvik  KO, Bilenberg  N.  A Danish population-based twin study on autism spectrum disorders.  Eur Child Adolesc Psychiatry. 2014;23(1):35-43.PubMedArticle
4.
Lichtenstein  P, Carlström  E, Råstam  M, Gillberg  C, Anckarsäter  H.  The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.  Am J Psychiatry. 2010;167(11):1357-1363.PubMedArticle
5.
Hallmayer  J, Cleveland  S, Torres  A,  et al.  Genetic heritability and shared environmental factors among twin pairs with autism.  Arch Gen Psychiatry. 2011;68(11):1095-1102.PubMedArticle
6.
Sandin  S, Lichtenstein  P, Kuja-Halkola  R, Larsson  H, Hultman  CM, Reichenberg  A.  The familial risk of autism.  JAMA. 2014;311(17):1770-1777.PubMedArticle
7.
Brown  AS, Surcel  HM, Hinkka-Yli-Salomäki  S, Cheslack-Postava  K, Bao  Y, Sourander  A.  Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort.  Prog Neuropsychopharmacol Biol Psychiatry. 2015;57(57):86-92.PubMedArticle
8.
Polo-Kantola  P, Lampi  KM, Hinkka-Yli-Salomäki  S, Gissler  M, Brown  AS, Sourander  A.  Obstetric risk factors and autism spectrum disorders in Finland.  J Pediatr. 2014;164(2):358-365.PubMedArticle
9.
Lampi  KM, Lehtonen  L, Tran  PL,  et al.  Risk of autism spectrum disorders in low birth weight and small for gestational age infants.  J Pediatr. 2012;161(5):830-836.PubMedArticle
10.
Hultman  CM, Sparén  P, Cnattingius  S.  Perinatal risk factors for infantile autism.  Epidemiology. 2002;13(4):417-423.PubMedArticle
11.
Jokiranta  E, Brown  AS, Heinimaa  M, Cheslack-Postava  K, Suominen  A, Sourander  A.  Parental psychiatric disorders and autism spectrum disorders.  Psychiatry Res. 2013;207(3):203-211.PubMedArticle
12.
Ozonoff  S, Young  GS, Carter  A,  et al.  Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study.  Pediatrics. 2011;128(3):e488-e495.PubMed
13.
Sullivan  PF, Magnusson  C, Reichenberg  A,  et al.  Family history of schizophrenia and bipolar disorder as risk factors for autism.  Arch Gen Psychiatry. 2012;69(11):1099-1103.PubMedArticle
14.
Selten  JP, Lundberg  M, Rai  D, Magnusson  C.  Risks for nonaffective psychotic disorder and bipolar disorder in young people with autism spectrum disorder: a population-based study.  JAMA Psychiatry. 2015;72(5):483-489.PubMedArticle
15.
Simonoff  E, Pickles  A, Charman  T, Chandler  S, Loucas  T, Baird  G.  Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample.  J Am Acad Child Adolesc Psychiatry. 2008;47(8):921-929.PubMedArticle
16.
Casey  BJ, Oliveri  ME, Insel  T.  A neurodevelopmental perspective on the research domain criteria (RDoC) framework.  Biol Psychiatry. 2014;76(5):350-353.PubMedArticle
17.
Craddock  N, Owen  MJ.  The Kraepelinian dichotomy—going, going... but still not gone.  Br J Psychiatry. 2010;196(2):92-95.PubMedArticle
18.
Lampi  KM, Banerjee  PN, Gissler  M,  et al.  Finnish prenatal study of autism and autism spectrum disorders (FIPS-A): overview and design.  J Autism Dev Disord. 2011;41(8):1090-1096.PubMedArticle
19.
World Health Organization.  International Classification of Diseases, Eighth Revision. Geneva, Switzerland: World Health Organization; 1967.
20.
World Health Organization.  International Classification of Diseases, Ninth Revision. Geneva, Switzerland: World Health Organization; 1977.
21.
Lehti  V, Hinkka-Yli-Salomäki  S, Cheslack-Postava  K, Gissler  M, Brown  AS, Sourander  A.  Maternal socio-economic status based on occupation and autism spectrum disorders: a national case-control study.  Nord J Psychiatry. 2015;69(7):523-530.PubMedArticle
22.
Gilman  SE, Kawachi  I, Fitzmaurice  GM, Buka  SL.  Socioeconomic status in childhood and the lifetime risk of major depression.  Int J Epidemiol. 2002;31(2):359-367.PubMedArticle
23.
Lampi  KM, Hinkka-Yli-Salomäki  S, Lehti  V,  et al.  Parental age and risk of autism spectrum disorders in a Finnish national birth cohort.  J Autism Dev Disord. 2013;43(11):2526-2535.PubMedArticle
24.
Rantakallio  P.  Social background of mothers who smoke during pregnancy and influence of these factors on the offspring.  Soc Sci Med. 1979;13A(4):423-429.PubMed
25.
Liang  KY, Zeger  SL.  Longitudinal data analysis using generalized linear models.  Biometrika. 1986;73(1):13-22.Article
26.
SAS Institute Inc. SAS, Version 9.4 [computer program]. Cary, NC: SAS Institute Inc; 2010.
27.
Grønborg  TK, Schendel  DE, Parner  ET.  Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study.  JAMA Pediatr. 2013;167(10):947-953.PubMedArticle
28.
Georgiades  S, Szatmari  P, Zwaigenbaum  L,  et al.  A prospective study of autistic-like traits in unaffected siblings of probands with autism spectrum disorder.  JAMA Psychiatry. 2013;70(1):42-48.PubMedArticle
29.
August  GJ, Stewart  MA, Tsai  L.  The incidence of cognitive disabilities in the siblings of autistic children.  Br J Psychiatry. 1981;138(5):416-422.PubMedArticle
30.
Piven  J, Gayle  J, Chase  GA,  et al.  A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals.  J Am Acad Child Adolesc Psychiatry. 1990;29(2):177-183.PubMedArticle
31.
Minton  J, Campbell  M, Green  WH, Jennings  S, Samit  C.  Cognitive assessment of siblings of autistic children.  J Am Acad Child Psychiatry. 1982;21(3):256-261.PubMedArticle
32.
Fombonne  E, Bolton  P, Prior  J, Jordan  H, Rutter  M.  A family study of autism: cognitive patterns and levels in parents and siblings.  J Child Psychol Psychiatry. 1997;38(6):667-683.PubMedArticle
33.
Folstein  SE, Santangelo  SL, Gilman  SE,  et al.  Predictors of cognitive test patterns in autism families.  J Child Psychol Psychiatry. 1999;40(7):1117-1128.PubMedArticle
34.
Szatmari  P, Jones  MB, Tuff  L, Bartolucci  G, Fisman  S, Mahoney  W.  Lack of cognitive impairment in first-degree relatives of children with pervasive developmental disorders.  J Am Acad Child Adolesc Psychiatry. 1993;32(6):1264-1273.PubMedArticle
35.
Pilowsky  T, Yirmiya  N, Gross-Tsur  V, Shalev  RS.  Neuropsychological functioning of siblings of children with autism, siblings of children with developmental language delay, and siblings of children with mental retardation of unknown genetic etiology.  J Autism Dev Disord. 2007;37(3):537-552.PubMedArticle
36.
Ozonoff  S, Rogers  SJ, Farnham  JM, Pennington  BF.  Can standard measures identify subclinical markers of autism?  J Autism Dev Disord. 1993;23(3):429-441.PubMedArticle
37.
Pilowsky  T, Yirmiya  N, Shalev  RS, Gross-Tsur  V.  Language abilities of siblings of children with autism.  J Child Psychol Psychiatry. 2003;44(6):914-925.PubMedArticle
38.
McGuffin  P, Rijsdijk  F, Andrew  M, Sham  P, Katz  R, Cardno  A.  The heritability of bipolar affective disorder and the genetic relationship to unipolar depression.  Arch Gen Psychiatry. 2003;60(5):497-502.PubMedArticle
39.
Sullivan  PF, Kendler  KS, Neale  MC.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.  Arch Gen Psychiatry. 2003;60(12):1187-1192.PubMedArticle
40.
Brown  AS, Sourander  A, Hinkka-Yli-Salomäki  S, McKeague  IW, Sundvall  J, Surcel  HM.  Elevated maternal C-reactive protein and autism in a national birth cohort.  Mol Psychiatry. 2014;19(2):259-264.PubMedArticle
41.
Brown  AS.  Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.  Dev Neurobiol. 2012;72(10):1272-1276.PubMedArticle
42.
Cannon  M, Jones  PB, Murray  RM.  Obstetric complications and schizophrenia: historical and meta-analytic review.  Am J Psychiatry. 2002;159(7):1080-1092.PubMedArticle
43.
Nosarti  C, Reichenberg  A, Murray  RM,  et al.  Preterm birth and psychiatric disorders in young adult life.  Arch Gen Psychiatry. 2012;69(6):E1-E8.PubMedArticle
44.
Laursen  TM, Munk-Olsen  T, Nordentoft  M, Bo Mortensen  P.  A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a Danish population-based cohort.  J Clin Psychiatry. 2007;68(11):1673-1681.PubMedArticle
45.
Chudal  R, Gissler  M, Sucksdorff  D,  et al.  Parental age and the risk of bipolar disorders.  Bipolar Disord. 2014;16(6):624-632.PubMedArticle
46.
McGrath  JJ, Petersen  L, Agerbo  E, Mors  O, Mortensen  PB, Pedersen  CB.  A comprehensive assessment of parental age and psychiatric disorders.  JAMA Psychiatry. 2014;71(3):301-309.PubMedArticle
47.
Rapoport  J, Chavez  A, Greenstein  D, Addington  A, Gogtay  N.  Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited.  J Am Acad Child Adolesc Psychiatry. 2009;48(1):10-18.PubMedArticle
48.
Ståhlberg  O, Söderström  H, Råstam  M, Gillberg  C.  Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders.  J Neural Transm (Vienna). 2004;111(7):891-902.PubMed
49.
Moreno-De-Luca  D, Mulle  JG, Kaminsky  EB,  et al; SGENE Consortium; Simons Simplex Collection Genetics Consortium; GeneSTAR.  Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.  Am J Hum Genet. 2010;87(5):618-630.PubMedArticle
50.
Lichtenstein  P, Yip  BH, Björk  C,  et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.  Lancet. 2009;373(9659):234-239.PubMedArticle
51.
Carroll  LS, Owen  MJ.  Genetic overlap between autism, schizophrenia and bipolar disorder.  Genome Med. 2009;1(10):102.PubMedArticle
52.
Lee  SH, Ripke  S, Neale  BM,  et al; Cross-Disorder Group of the Psychiatric Genomics Consortium; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC).  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.  Nat Genet. 2013;45(9):984-994.PubMedArticle
53.
Tran  PL, Lehti  V, Lampi  KM,  et al.  Smoking during pregnancy and risk of autism spectrum disorder in a Finnish National Birth Cohort.  Paediatr Perinat Epidemiol. 2013;27(3):266-274.PubMedArticle
54.
Jokiranta  E, Sourander  A, Suominen  A, Timonen-Soivio  L, Brown  AS, Sillanpää  M.  Epilepsy among children and adolescents with autism spectrum disorders: a population-based study.  J Autism Dev Disord. 2014;44(10):2547-2557.PubMedArticle
55.
Quintero  N, McIntyre  LL.  Sibling adjustment and maternal well-being: an examination of families with and without a child with an autism spectrum disorder.  Focus Autism Other Dev Disabl. 2010;25(1):37-46.PubMed
56.
Joelsson  P, Chudal  R, Gyllenberg  D,  et al.  Demographic characteristics and psychiatric comorbidity of children and adolescents diagnosed with ADHD in specialized healthcare [published online September 23, 2015].  Child Psychiatry Hum Dev. doi:10.1007/s10578-015-0591-6.PubMed
57.
Lampi  KM, Sourander  A, Gissler  M,  et al.  Brief report: validity of Finnish registry-based diagnoses of autism with the ADI-R.  Acta Paediatr. 2010;99(9):1425-1428.PubMedArticle
58.
Leivonen  S, Voutilainen  A, Hinkka-Yli-Salomäki  S,  et al.  A nationwide register study of the characteristics, incidence and validity of diagnosed Tourette syndrome and other tic disorders.  Acta Paediatr. 2014;103(9):984-990.PubMedArticle
59.
Sund  R.  Quality of the Finnish Hospital Discharge Register: a systematic review.  Scand J Public Health. 2012;40(6):505-515.PubMedArticle
60.
Sourander  A, Helstelä  L, Ristkari  T, Ikäheimo  K, Helenius  H, Piha  J.  Child and adolescent mental health service use in Finland.  Soc Psychiatry Psychiatr Epidemiol. 2001;36(6):294-298.PubMedArticle
61.
Sourander  A, Santalahti  P, Haavisto  A, Piha  J, IkÄheimo  K, Helenius  H.  Have there been changes in children’s psychiatric symptoms and mental health service use? a 10-year comparison from Finland.  J Am Acad Child Adolesc Psychiatry. 2004;43(9):1134-1145.PubMedArticle
Original Investigation
June 2016

Risk of Psychiatric and Neurodevelopmental Disorders Among Siblings of Probands With Autism Spectrum Disorders

Author Affiliations
  • 1Department of Child Psychiatry, University of Turku, Turku University Hospital, Turku, Finland
  • 2Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, New York, New York
  • 3National Institute for Health and Welfare, Helsinki, Finland
  • 4Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York
JAMA Psychiatry. 2016;73(6):622-629. doi:10.1001/jamapsychiatry.2016.0495
Abstract

Importance  Previous research has focused on examining the familial clustering of schizophrenia, bipolar disorder, and autism spectrum disorders (ASD). Little is known about the clustering of other psychiatric and neurodevelopmental disorders among siblings of persons with ASD.

Objective  To examine the risk for psychiatric and neurodevelopmental disorders among full siblings of probands with ASD.

Design, Setting, and Participants  The Finnish Prenatal Study of Autism and Autism Spectrum Disorders used a population-based cohort that included children born from January 1, 1987, to December 31, 2005, who received a diagnosis of ASD by December 31, 2007. Each case was individually matched to 4 control participants by sex and date and place of birth. The siblings of the cases and controls were born from January 1, 1977, to December 31, 2005, and received a diagnosis from January 1, 1987, to December 31, 2009. This nested case-control study included 3578 cases with ASD with 6022 full siblings and 11 775 controls with 22 127 siblings from Finnish national registers. Data were analyzed from March 6, 2014, to February 12, 2016.

Main Outcomes and Measures  The adjusted risk ratio (RR) for psychiatric and neurodevelopmental disorders among siblings of probands with ASD vs siblings of matched controls. Additional analyses were conducted separately for ASD subgroups, including childhood autism, Asperger syndrome, and pervasive developmental disorders not otherwise specified. Analyses were further stratified by sex and intellectual disability among the probands.

Results  Among the 3578 cases with ASD (2841 boys [79.4%]) and 11 775 controls (9345 boys [79.4%]), 1319 cases (36.9%) and 2052 controls (17.4%) had at least 1 sibling diagnosed with any psychiatric or neurodevelopmental disorder (adjusted RR, 2.5; 95% CI, 2.3-2.6). The largest associations were observed for childhood-onset disorders (1061 cases [29.7%] vs 1362 controls [11.6%]; adjusted RR, 3.0; 95% CI, 2.8-3.3), including ASD (374 cases [10.5%] vs 125 controls [1.1%]; adjusted RR, 11.8; 95% CI, 9.4-14.7), tic disorders (28 cases [0.8%] vs 24 controls [0.2%]; adjusted RR, 4.3; 95% CI, 2.3-8.2), attention-deficit/hyperactivity disorder (189 cases [5.3%] vs 180 controls [1.5%]; adjusted RR, 3.7; 95% CI, 2.9-4.7), learning and coordination disorders (563 cases [15.7%] vs 697 controls [5.9%]; adjusted RR, 3.2; 95% CI, 2.8-3.6), intellectual disability (104 cases [2.9%] vs 137 controls [1.2%]; adjusted RR, 3.1; 95% CI, 2.3-4.2), conduct and oppositional disorders (180 cases [5.0%] vs 221 controls [1.9%]; adjusted RR, 2.8; 95% CI, 2.2-3.5), and emotional disorders with onset specific to childhood (126 cases [3.5%] vs 157 controls [1.3%]; adjusted RR, 2.6; 95% CI, 1.9-3.4). Autism spectrum disorders were also associated with schizophrenia spectrum disorders, affective disorders, anxiety disorders, and other neurotic and personality disorders among siblings.

Conclusions and Relevance  Psychiatric and neurodevelopmental disorders cluster among siblings of probands with ASD. For etiologic research, these findings provide further evidence that several psychiatric and neurodevelopmental disorders have common risk factors.

Introduction

Autism spectrum disorders (ASD) represent a group of complex, early-onset neurodevelopmental disorders that are characterized by qualitative abnormalities in social interaction and communication, stereotypic, repetitive behavior, and narrow interests.1 Although genetic factors play a strong role in the etiology of ASD,24 previous studies5,6 reported a substantial role for environmental factors. In addition, evidence from population-based studies has implicated prenatal factors in the development of ASD.710

Parental psychiatric disorders, particularly schizophrenia and affective disorders, increase the risk for ASD in offspring.11 Similarly, schizophrenia, bipolar disorder, and ASD among siblings are associated with ASD.6,1214 However, research investigating other psychiatric and neurodevelopmental disorders among siblings of individuals with ASD is lacking. Autism spectrum disorders frequently co-occur with a range of other disorders such as intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), behavioral disturbances, and anxiety disorders.15 Thus, we can plausibly hypothesize that siblings of individuals with ASD could have genetically and/or environmentally mediated vulnerability to many different types of psychiatric and neurodevelopmental disorders. This hypothesis has gained support from a twin study,4 which concluded that when 1 dizygotic twin had been diagnosed with ASD, the probability in the co-twin for ADHD was 15%; for developmental coordination disorder, 12%; and for tic and learning disorders, 10%. To our knowledge, no other nationwide population-based study has examined the clustering of the whole spectrum of psychiatric and neurodevelopmental disorders among siblings of probands with ASD. Investigating a broader range of different psychiatric and neurodevelopmental disorders among the siblings of children with ASD provides guidance for clinical assessment, prevention, treatment, and etiologic research.16,17

Our first aim was to examine the psychiatric and neurodevelopmental disorders among full siblings of probands with ASD by using a nationwide population-based sample, including cases and matched control individuals. We further conducted the examination for subgroups of ASD, namely probands with childhood autism, Asperger syndrome, and pervasive developmental disorders not otherwise specified (PDD-NOS). Another aim was to analyze the associations stratified by sex and the presence of co-occurring ID among cases. We hypothesized that ASD would be associated with several disorders among siblings, particularly those disorders that frequently co-occur with ASD.

Box Section Ref ID

Key Points

  • Question Do siblings of probands with autism spectrum disorders (ASD) receive more frequent diagnoses of psychiatric and neurodevelopmental disorders than siblings of healthy controls?

  • Findings This population-based, cohort case-control study compared 3578 cases with ASD and their 6022 siblings with 11 775 controls and their 22 127 full siblings. The siblings of cases with ASD showed elevated rates of all childhood-onset disorders investigated and of schizophrenia spectrum disorders, affective disorders, anxiety disorders, and other neurotic and personality disorders.

  • Meaning These findings provide further evidence that several psychiatric and neurodevelopmental disorders have common risk factors.

Methods
Data Sources

This study is part of the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A), a nested case-control study based on a national birth cohort. The total cohort includes nearly 1.2 million singleton births in Finland from January 1, 1987, to December 31, 2005. Children were followed up until December 31, 2007, for the diagnosis of ASD. The study was expanded later to include the data of siblings, who have different time frames for follow-up. Linkages between nationwide registers used the unique personal identity codes that are given at birth to every Finnish resident and remain the same throughout the lifespan. The FIPS-A has received approval from the Ethical Committee of the Hospital District of Southwest Finland and from the institutional review board of the New York State Psychiatric Institute. The use of register data for this research has been authorized by the Ministry of Social Affairs and Health in Finland and the National Institute for Health and Welfare.

Data were collected from the following 3 nationwide registers: the Finnish Hospital Discharge Register (FHDR), the Finnish Medical Birth Register (FMBR), and the Finnish Population Register Centre (FPRC). Registers and the study design have been described in detail previously.18

The FHDR contains the primary diagnosis and additional subsidiary diagnoses at discharge from an inpatient unit and for every visit to an outpatient unit. Starting from 1969, the FHDR covers all inpatient care units in Finland. Since 1998, the FHDR also includes outpatient care in public specialized hospital units. Diagnoses are based on the International Classification of Diseases, Eighth Revision, from 1969 to 198619; International Classification of Diseases, Ninth Revision (ICD-9), from 1987 to 199520; and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), from 1996 onward.1 The FHDR was used to identify children diagnosed as having ASD and the psychiatric and/or neurodevelopmental disorders among the siblings of cases and controls and to obtain data on covariates.

The FMBR, established in 1987, includes comprehensive maternal, fetal, and newborn health–related standardized data on every live birth collected during pregnancy to 7 days of age. The FMBR was used to identify the controls and the mothers and to obtain the data on covariates. The FPRC is a computerized nationwide register maintained by the Finnish population center and local register offices. It contains basic information (eg, name, family relations, and deaths, if applicable) about Finnish residents and foreign citizens living permanently in Finland. Data from the FPRC were used to identify the fathers and the full siblings of the probands and controls.

Identification of Cases, Controls, and Siblings

The eFigure in the Supplement shows the selection of the study sample. Children with ASD (n = 4704) were identified from the FHDR using ICD-9 and ICD-10 codes. The most recent diagnosis was used and all but 19 cases were diagnosed using ICD-10 codes. The ASD group included children diagnosed as having childhood autism (ICD-10 code F84.0) (n = 1130), Asperger syndrome (ICD-10 code F84.5) (n = 1783), or PDD-NOS (ICD-10 codes F84.8-F84.9) (n = 1791). Each case was matched to 4 controls by date of birth (±30 days), sex, and place of birth as identified from the FMBR. Exclusion criteria were a diagnosis with severe or profound ID or ASD or having died or emigrated from Finland before the case was diagnosed. In total, 18 677 matched controls were identified.

As shown in the eFigure in the Supplement, a total of 3578 cases with ASD with 6022 full siblings and 11 775 controls with 22 127 full siblings were included in the analysis. The siblings were born from January 1, 1977, to December 31, 2005, and diagnosed from January 1, 1987, to December 31, 2009. Siblings born before 1977 or after 2005 were excluded.

Diagnoses Among Siblings

The diagnoses among the siblings were first assessed using a dichotomous variable (no or yes for any psychiatric or neurodevelopmental disorder). Then the specific disorders were assessed, as presented in eTable 1 in the Supplement. Similarly, the category of childhood-onset disorders was also first assessed using a dichotomous variable (no or yes for any disorder usually diagnosed in childhood), then examined by specific disorders (eTable 1 in the Supplement). In case of co-occurring disorders, such as a diagnosis of affective disorder and ADHD, the sibling was categorized as having each of these disorders.

Covariates

Covariates were considered for inclusion in the analysis based on the previous findings.11,2123 Covariates included in the analysis were maternal socioeconomic status21,22 based on maternal occupation, parental psychiatric diagnoses,11 and parental age.23 Maternal socioeconomic status was chosen because in Finland it is a stronger indicator of the family’s socioeconomic status than paternal occupation.24 A detailed description of covariates is presented in eTable 2 in the Supplement.

Statistical Analysis

Data were analyzed from March 6, 2014, to February 12, 2016. We conducted bivariate analysis using the Pearson χ2 test to evaluate the significance of associations between the covariates and (1) any psychiatric or neurodevelopmental disorders in the siblings, among controls only, and (2) ASD. The Wilcoxon rank sum test was used to compare the age at first diagnosis among siblings of cases with that of siblings of controls. We conducted Pearson χ2 tests to examine whether the sizes of the sibships differed between cases and controls.

Separately for each outcome, regression models were fit to estimate the association between ASD in children and psychiatric or neurodevelopmental disorders in their siblings. The unit of analysis was the sibling. Generalized estimating equations were used to account for the dependency between cases and matched controls and the siblings within the same family. The stratum was defined by the matched case-control set; therefore, each stratum included siblings of 1 case and of the matched controls. Poisson regression analyses with a log-link function were fit.25 The outcome variable was a dichotomous (no or yes) measure for the disorders in the sibling. The exposure variable was the case or control status of the proband. The estimation of model parameters was regressed using follow-up years as an offset to account for length of follow-up of siblings. The relation of ASD status to the outcome was reported as risk ratios (RRs) with 95% CIs. Two-sided P values with statistical significance of less than .05 were calculated using the Pearson χ2 test.

The first model was unadjusted; the second model was adjusted with covariates (eTable 2 in the Supplement). These models were first fit using the complete data. The data were then stratified by subgroups of ASD, sex, and ID among cases. The interaction term was assessed to compare the magnitude of RRs for disorders in siblings between female vs male probands. Finally, siblings diagnosed with ASD were excluded from the analysis to confirm that our findings were not due solely to ASD among siblings. All the analyses were conducted using SAS statistical software.26

Results

All covariates tested were associated with any psychiatric or neurodevelopmental disorder among siblings and ASD case status (eTable 2 in the Supplement). We included 3578 cases with ASD (2841 boys [79.4%]) and 11 775 controls (9345 boys [79.4%]). Table 1 shows the characteristics of the siblings of cases and controls and demonstrates a larger sibship among controls (P < .001) except for PDD-NOS (P = .32).

Table 2 shows the mean age at first diagnosis for different disorders among the siblings of cases and controls. Siblings of cases received the diagnosis earlier than did siblings of controls in most of the disorders. Of the cases, 1319 of 3578 (36.9%) had at least 1 sibling diagnosed as having any psychiatric or neurodevelopmental disorder, whereas the corresponding figure among controls was 2052 of 11 775 (17.4%) (adjusted RR, 2.5; 95% CI, 2.3-2.6) (Table 2). For childhood-onset disorders, 1061 of 3578 cases (29.7%) had at least 1 sibling diagnosed vs 1362 of 11 775 controls (11.6%) (adjusted RR, 3.0; 95% CI, 2.8-3.3). Increased risk was demonstrated in all examined disorders except alcohol and drug addiction or abuse. The strongest risks were observed with ASD, tic disorders, ADHD, learning and coordination disorders, and ID. The exclusion of siblings diagnosed as having obsessive-compulsive disorder from the anxiety category did not change the results (adjusted RR, 1.6; 95% CI, 1.2-2.0; P < .001).

Table 3 shows that most of the associations were present among siblings of cases with and without co-occurring ID and showed similarities in the associations. The RRs for some disorders could not be estimated owing to too few numbers of observations or lack of complete covariate data.

Adjusted associations of childhood autism, Asperger syndrome, PDD-NOS, and psychiatric or neurodevelopmental disorders among siblings are presented in Table 4. All ASD subgroups were associated with the main categories of disorders, that is, any psychiatric or neurodevelopmental disorders and childhood-onset disorders. Similar increased risks for ASD in the siblings were observed in all ASD subgroups. However, we found discrepancies in the other disorders examined. Results of the analysis by sex and with the exclusion of siblings with ASD are given in eTables 3 and 4 and discussed in the eResults in the Supplement.

Discussion

The rates of all investigated psychiatric and neurodevelopmental disorders except alcohol and drug addiction or abuse were elevated among the siblings of cases with ASD compared with the siblings of controls. The strongest associations were observed for childhood-onset disorders. The associations were present also among the siblings of cases with ASD without co-occurring ID. Childhood autism, Asperger syndrome, and PDD-NOS showed similar associations with childhood-onset disorders but not with the other disorders examined. No differences in the risk for psychopathology were observed between the siblings of male and female probands.

All childhood-onset disorders examined, including ASD, ADHD, ID, childhood emotional disorders, learning and coordination disorders, conduct and oppositional disorders, and tic disorders, were more frequent among siblings of cases with ASD. The elevated rates of ASD observed among siblings of children with ASD are in line with rates in the existing literature.6,27 Before this study, only 1 population-based study,4 which was conducted among twins, has examined some of these childhood-onset disorders. Our results are in accordance with the findings in that study,4 which showed that among dizygotic twins the risk for childhood-onset disorders was increased when 1 twin was diagnosed as having ASD. To our knowledge, ID has not been examined previously among siblings of probands in other population-based studies. Clinical studies examining cognitive impairments among siblings of probands are difficult to generalize because their results are inconsistent. Although some studies have found lower cognitive abilities,2832 others have not found differences.3336 Moreover, some studies have found even higher verbal IQ levels among the siblings of probands than among the siblings of controls.32,37 Thus, the finding of elevated rates of ID among siblings of probands needs to be replicated in other population-based studies. Shared genetic factors have been suggested to explain a significant proportion of the comorbidity between ASD and other childhood disorders,4 which might explain the clustering of these disorders among the siblings. Traditionally different childhood-onset disorders are considered to be discrete entities. However, the symptoms seen among patients are often complex and overlap with each other. The fact that probands with ASD themselves are at increased risk for these childhood-onset disorders and that these disorders cluster between family members indicate that different childhood-onset disorders might be etiologically more similar than currently believed and have common risk factors.

The associations observed for siblings’ schizophrenia spectrum disorders and affective disorders are in line with observations in the studies conducted in Sweden.13,14 A recent study using a similar epidemiologic sample14 found nearly 2-fold increased odds for nonaffective psychotic disorders and bipolar disorder among the siblings of children with ASD. Parental schizophrenia and affective disorders are associated with ASD among offspring,11 and the associations of these disorders were observed here among siblings, even when we controlled for parental psychiatric diagnoses. Our findings showing higher rates of schizophrenia and affective disorders among the siblings of cases with ASD vs the siblings of controls give further support to the view that ASD, schizophrenia, and bipolar disorder share common etiologic risk factors. The heritability for these disorders is estimated to be high,24,38,39 and certain shared environmental risk factors have been associated with these disorders, such as prenatal infection or inflammation,40,41 obstetric or perinatal complications,8,4244 and parental age.23,45,46 In addition, children with ASD are at an increased risk for schizophrenia and bipolar disorder.14,47,48 These findings may also reflect a common underlying genetic vulnerability for these disorders.14,4952 On the other hand, as hypothesized recently,14 environmental factors, such as psychological stress resulting from the impairments associated with ASD, might mediate the risk for psychosis.

Childhood autism, Asperger syndrome, and PDD-NOS were all associated with the main categories of disorders, that is, any psychiatric or neurodevelopmental disorder and any childhood-onset disorder among siblings. Moreover, the rates of ASD in siblings were increased not only in childhood autism but also in Asperger syndrome and PDD-NOS. However, we found discrepancies between these ASD subgroups in the specific disorders examined; PDD-NOS was associated with all disorders examined except substance abuse. Asperger syndrome was associated with most of the disorders, whereas the associations with childhood autism were primarily seen among childhood-onset disorders. Previous studies have also shown variations in the risks for these ASD subgroups with factors such as obstetric complications,8 maternal smoking,53 parental age,23 parental psychiatric diagnoses,11 and comorbid epilepsy.54 These variations point toward a possible etiologic heterogeneity resulting in the phenotypic variations observed in ASD.

An ASD diagnosis in 1 child could lead to a closer monitoring of their siblings, which in turn could partially account for the association seen in our results. In addition, as parents’ awareness about psychiatric and neurodevelopmental disorders increase through learning and seeking treatment for their child’s ASD, they might more readily seek help for siblings than parents who do not have a child with ASD. On the other hand, when siblings diagnosed with ASD were excluded from the analyses, the mean age at diagnosis, especially in childhood-onset disorders, did not differ between the siblings of cases and the siblings of controls. Another factor that might explain some of the findings is the familial stress related to ASD. By increasing the stress and parental conflict, ASD that affects 1 child may increase the siblings’ risk for disorders such as anxiety and externalizing problems.55

The strengths of this study include a large, population-based sample consisting of patients from inpatient and outpatient settings, together with data on covariates. This study design reduces the potential for bias, including reporting and recall bias and loss to follow-up, thus increasing the generalizability of the findings.

The findings should be interpreted in light of the following limitations. First, some diagnoses may be misclassified. However, the FHDR has shown good validity for several disorders, including ASD, ADHD, and tic disorders.5659 Second, the FHDR includes inpatient diagnoses since 1969 and outpatient diagnoses from 1998. We assume, however, that we have captured many probands treated for the first time as outpatients before 1998, because ASD is a chronic condition, and by using the latest recorded diagnosis, the cases will subsequently be registered in the FHDR. Third, we found an unequal follow-up time in the study for cases, controls, and siblings, with the youngest siblings being followed up only for 4 years. Therefore, the whole cohort was not followed up throughout the period at risk for adulthood disorders (eg, schizophrenia and bipolar disorder). Finally, the use of health care services among the siblings of probands with ASD may differ from the use of services by the siblings of the controls. In addition, the FHDR includes children referred to specialized services, skewing the data toward more severe conditions. Less severe conditions, such as mild anxiety, which may be treated only in primary health care or private clinics, are not included in the FHDR. We expect, however, that coverage of moderate and severe neurodevelopmental or psychiatric disorders is high, for 2 reasons. First, before the beginning of school at 7 years of age, virtually all children visit the municipal child health clinics at least once a year. The suspicion of neurodevelopmental or psychiatric symptoms leads to the referral to hospital clinics, including specialized services. Second, the Finnish universal health care system is based on public services, independent of parental income.60,61 Therefore, children with moderate or severe symptoms of neurodevelopmental or psychiatric disorders will most likely be referred to specialized services and subsequently registered in the FHDR.

Conclusions

This study shows that all childhood-onset disorders investigated and schizophrenia spectrum disorders, affective disorders, anxiety disorders, and other neurotic and personality disorders occur at increased frequency in the siblings of individuals with ASD. Further, similarities in the magnitudes of the associations were observed among the siblings of cases with and without co-occurring ID. Subgroups of ASD showed similar associations with childhood-onset disorders, whereas we found discrepancies among the other disorders examined. The risk for psychopathology did not differ among the siblings of male and female probands. Health care professionals working with the families of individuals with ASD should pay particular attention to the siblings of probands and provide support for the whole family. For etiologic research, the findings provide further evidence that several psychiatric and neurodevelopmental disorders have common risk factors.

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Article Information

Corresponding Author: Elina Jokiranta-Olkoniemi, MA, Department of Child Psychiatry, University of Turku, Turku University Hospital, Lemminkäisenkatu 3 Teutori, 20014 Turku, Finland (ekjoki@utu.fi).

Submitted for Publication: September 11, 2015; final revision received February 16, 2016; accepted February 17, 2016.

Published Online: May 4, 2016. doi:10.1001/jamapsychiatry.2016.0495.

Author Contributions: Ms Suominen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jokiranta-Olkoniemi, Chudal, Brown, Sourander.

Acquisition, analysis, or interpretation of data: Jokiranta-Olkoniemi, Cheslack-Postava, Sucksdorff, Suominen, Gyllenberg, Leivonen, Gissler, Brown, Sourander.

Drafting of the manuscript: Jokiranta-Olkoniemi, Brown, Sourander.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Suominen, Gyllenberg, Gissler.

Obtained funding: Jokiranta-Olkoniemi, Brown, Sourander.

Administrative, technical, or material support: Sucksdorff, Suominen, Chudal.

Study supervision: Gissler, Sourander.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants from University of Turku Graduate School (Ms Jokiranta-Olkoniemi and Dr Leivonen), Emil Aaltonen Foundation (Ms Jokiranta-Olkoniemi), Päivikki and Sakari Sohlberg Foundation (Ms Jokiranta-Olkoniemi), Orion Pharma Foundation (Drs Chudal and Leivonen), Yrjö Jahnsson Foundation (Dr Chudal), Jalmari and Rauha Ahokas Foundation (Dr Chudal), and Finnish Brain Foundation (Dr Leivonen) and grant R01ES019004 from the National Institute of Environmental Health Sciences (Dr Brown).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Previous Presentation: This paper was presented in part at the Nordic Child and Adolescent Psychiatric Research Meeting; September 10, 2014; Middelfart, Denmark.

References
1.
World Health Organization.  International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Geneva, Switzerland: World Health Organization; 1992.
2.
Colvert  E, Tick  B, McEwen  F,  et al.  Heritability of autism spectrum disorder in a UK population-based twin sample.  JAMA Psychiatry. 2015;72(5):415-423.PubMedArticle
3.
Nordenbæk  C, Jørgensen  M, Kyvik  KO, Bilenberg  N.  A Danish population-based twin study on autism spectrum disorders.  Eur Child Adolesc Psychiatry. 2014;23(1):35-43.PubMedArticle
4.
Lichtenstein  P, Carlström  E, Råstam  M, Gillberg  C, Anckarsäter  H.  The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.  Am J Psychiatry. 2010;167(11):1357-1363.PubMedArticle
5.
Hallmayer  J, Cleveland  S, Torres  A,  et al.  Genetic heritability and shared environmental factors among twin pairs with autism.  Arch Gen Psychiatry. 2011;68(11):1095-1102.PubMedArticle
6.
Sandin  S, Lichtenstein  P, Kuja-Halkola  R, Larsson  H, Hultman  CM, Reichenberg  A.  The familial risk of autism.  JAMA. 2014;311(17):1770-1777.PubMedArticle
7.
Brown  AS, Surcel  HM, Hinkka-Yli-Salomäki  S, Cheslack-Postava  K, Bao  Y, Sourander  A.  Maternal thyroid autoantibody and elevated risk of autism in a national birth cohort.  Prog Neuropsychopharmacol Biol Psychiatry. 2015;57(57):86-92.PubMedArticle
8.
Polo-Kantola  P, Lampi  KM, Hinkka-Yli-Salomäki  S, Gissler  M, Brown  AS, Sourander  A.  Obstetric risk factors and autism spectrum disorders in Finland.  J Pediatr. 2014;164(2):358-365.PubMedArticle
9.
Lampi  KM, Lehtonen  L, Tran  PL,  et al.  Risk of autism spectrum disorders in low birth weight and small for gestational age infants.  J Pediatr. 2012;161(5):830-836.PubMedArticle
10.
Hultman  CM, Sparén  P, Cnattingius  S.  Perinatal risk factors for infantile autism.  Epidemiology. 2002;13(4):417-423.PubMedArticle
11.
Jokiranta  E, Brown  AS, Heinimaa  M, Cheslack-Postava  K, Suominen  A, Sourander  A.  Parental psychiatric disorders and autism spectrum disorders.  Psychiatry Res. 2013;207(3):203-211.PubMedArticle
12.
Ozonoff  S, Young  GS, Carter  A,  et al.  Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study.  Pediatrics. 2011;128(3):e488-e495.PubMed
13.
Sullivan  PF, Magnusson  C, Reichenberg  A,  et al.  Family history of schizophrenia and bipolar disorder as risk factors for autism.  Arch Gen Psychiatry. 2012;69(11):1099-1103.PubMedArticle
14.
Selten  JP, Lundberg  M, Rai  D, Magnusson  C.  Risks for nonaffective psychotic disorder and bipolar disorder in young people with autism spectrum disorder: a population-based study.  JAMA Psychiatry. 2015;72(5):483-489.PubMedArticle
15.
Simonoff  E, Pickles  A, Charman  T, Chandler  S, Loucas  T, Baird  G.  Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample.  J Am Acad Child Adolesc Psychiatry. 2008;47(8):921-929.PubMedArticle
16.
Casey  BJ, Oliveri  ME, Insel  T.  A neurodevelopmental perspective on the research domain criteria (RDoC) framework.  Biol Psychiatry. 2014;76(5):350-353.PubMedArticle
17.
Craddock  N, Owen  MJ.  The Kraepelinian dichotomy—going, going... but still not gone.  Br J Psychiatry. 2010;196(2):92-95.PubMedArticle
18.
Lampi  KM, Banerjee  PN, Gissler  M,  et al.  Finnish prenatal study of autism and autism spectrum disorders (FIPS-A): overview and design.  J Autism Dev Disord. 2011;41(8):1090-1096.PubMedArticle
19.
World Health Organization.  International Classification of Diseases, Eighth Revision. Geneva, Switzerland: World Health Organization; 1967.
20.
World Health Organization.  International Classification of Diseases, Ninth Revision. Geneva, Switzerland: World Health Organization; 1977.
21.
Lehti  V, Hinkka-Yli-Salomäki  S, Cheslack-Postava  K, Gissler  M, Brown  AS, Sourander  A.  Maternal socio-economic status based on occupation and autism spectrum disorders: a national case-control study.  Nord J Psychiatry. 2015;69(7):523-530.PubMedArticle
22.
Gilman  SE, Kawachi  I, Fitzmaurice  GM, Buka  SL.  Socioeconomic status in childhood and the lifetime risk of major depression.  Int J Epidemiol. 2002;31(2):359-367.PubMedArticle
23.
Lampi  KM, Hinkka-Yli-Salomäki  S, Lehti  V,  et al.  Parental age and risk of autism spectrum disorders in a Finnish national birth cohort.  J Autism Dev Disord. 2013;43(11):2526-2535.PubMedArticle
24.
Rantakallio  P.  Social background of mothers who smoke during pregnancy and influence of these factors on the offspring.  Soc Sci Med. 1979;13A(4):423-429.PubMed
25.
Liang  KY, Zeger  SL.  Longitudinal data analysis using generalized linear models.  Biometrika. 1986;73(1):13-22.Article
26.
SAS Institute Inc. SAS, Version 9.4 [computer program]. Cary, NC: SAS Institute Inc; 2010.
27.
Grønborg  TK, Schendel  DE, Parner  ET.  Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study.  JAMA Pediatr. 2013;167(10):947-953.PubMedArticle
28.
Georgiades  S, Szatmari  P, Zwaigenbaum  L,  et al.  A prospective study of autistic-like traits in unaffected siblings of probands with autism spectrum disorder.  JAMA Psychiatry. 2013;70(1):42-48.PubMedArticle
29.
August  GJ, Stewart  MA, Tsai  L.  The incidence of cognitive disabilities in the siblings of autistic children.  Br J Psychiatry. 1981;138(5):416-422.PubMedArticle
30.
Piven  J, Gayle  J, Chase  GA,  et al.  A family history study of neuropsychiatric disorders in the adult siblings of autistic individuals.  J Am Acad Child Adolesc Psychiatry. 1990;29(2):177-183.PubMedArticle
31.
Minton  J, Campbell  M, Green  WH, Jennings  S, Samit  C.  Cognitive assessment of siblings of autistic children.  J Am Acad Child Psychiatry. 1982;21(3):256-261.PubMedArticle
32.
Fombonne  E, Bolton  P, Prior  J, Jordan  H, Rutter  M.  A family study of autism: cognitive patterns and levels in parents and siblings.  J Child Psychol Psychiatry. 1997;38(6):667-683.PubMedArticle
33.
Folstein  SE, Santangelo  SL, Gilman  SE,  et al.  Predictors of cognitive test patterns in autism families.  J Child Psychol Psychiatry. 1999;40(7):1117-1128.PubMedArticle
34.
Szatmari  P, Jones  MB, Tuff  L, Bartolucci  G, Fisman  S, Mahoney  W.  Lack of cognitive impairment in first-degree relatives of children with pervasive developmental disorders.  J Am Acad Child Adolesc Psychiatry. 1993;32(6):1264-1273.PubMedArticle
35.
Pilowsky  T, Yirmiya  N, Gross-Tsur  V, Shalev  RS.  Neuropsychological functioning of siblings of children with autism, siblings of children with developmental language delay, and siblings of children with mental retardation of unknown genetic etiology.  J Autism Dev Disord. 2007;37(3):537-552.PubMedArticle
36.
Ozonoff  S, Rogers  SJ, Farnham  JM, Pennington  BF.  Can standard measures identify subclinical markers of autism?  J Autism Dev Disord. 1993;23(3):429-441.PubMedArticle
37.
Pilowsky  T, Yirmiya  N, Shalev  RS, Gross-Tsur  V.  Language abilities of siblings of children with autism.  J Child Psychol Psychiatry. 2003;44(6):914-925.PubMedArticle
38.
McGuffin  P, Rijsdijk  F, Andrew  M, Sham  P, Katz  R, Cardno  A.  The heritability of bipolar affective disorder and the genetic relationship to unipolar depression.  Arch Gen Psychiatry. 2003;60(5):497-502.PubMedArticle
39.
Sullivan  PF, Kendler  KS, Neale  MC.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies.  Arch Gen Psychiatry. 2003;60(12):1187-1192.PubMedArticle
40.
Brown  AS, Sourander  A, Hinkka-Yli-Salomäki  S, McKeague  IW, Sundvall  J, Surcel  HM.  Elevated maternal C-reactive protein and autism in a national birth cohort.  Mol Psychiatry. 2014;19(2):259-264.PubMedArticle
41.
Brown  AS.  Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism.  Dev Neurobiol. 2012;72(10):1272-1276.PubMedArticle
42.
Cannon  M, Jones  PB, Murray  RM.  Obstetric complications and schizophrenia: historical and meta-analytic review.  Am J Psychiatry. 2002;159(7):1080-1092.PubMedArticle
43.
Nosarti  C, Reichenberg  A, Murray  RM,  et al.  Preterm birth and psychiatric disorders in young adult life.  Arch Gen Psychiatry. 2012;69(6):E1-E8.PubMedArticle
44.
Laursen  TM, Munk-Olsen  T, Nordentoft  M, Bo Mortensen  P.  A comparison of selected risk factors for unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia from a Danish population-based cohort.  J Clin Psychiatry. 2007;68(11):1673-1681.PubMedArticle
45.
Chudal  R, Gissler  M, Sucksdorff  D,  et al.  Parental age and the risk of bipolar disorders.  Bipolar Disord. 2014;16(6):624-632.PubMedArticle
46.
McGrath  JJ, Petersen  L, Agerbo  E, Mors  O, Mortensen  PB, Pedersen  CB.  A comprehensive assessment of parental age and psychiatric disorders.  JAMA Psychiatry. 2014;71(3):301-309.PubMedArticle
47.
Rapoport  J, Chavez  A, Greenstein  D, Addington  A, Gogtay  N.  Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited.  J Am Acad Child Adolesc Psychiatry. 2009;48(1):10-18.PubMedArticle
48.
Ståhlberg  O, Söderström  H, Råstam  M, Gillberg  C.  Bipolar disorder, schizophrenia, and other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disorders.  J Neural Transm (Vienna). 2004;111(7):891-902.PubMed
49.
Moreno-De-Luca  D, Mulle  JG, Kaminsky  EB,  et al; SGENE Consortium; Simons Simplex Collection Genetics Consortium; GeneSTAR.  Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.  Am J Hum Genet. 2010;87(5):618-630.PubMedArticle
50.
Lichtenstein  P, Yip  BH, Björk  C,  et al.  Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.  Lancet. 2009;373(9659):234-239.PubMedArticle
51.
Carroll  LS, Owen  MJ.  Genetic overlap between autism, schizophrenia and bipolar disorder.  Genome Med. 2009;1(10):102.PubMedArticle
52.
Lee  SH, Ripke  S, Neale  BM,  et al; Cross-Disorder Group of the Psychiatric Genomics Consortium; International Inflammatory Bowel Disease Genetics Consortium (IIBDGC).  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.  Nat Genet. 2013;45(9):984-994.PubMedArticle
53.
Tran  PL, Lehti  V, Lampi  KM,  et al.  Smoking during pregnancy and risk of autism spectrum disorder in a Finnish National Birth Cohort.  Paediatr Perinat Epidemiol. 2013;27(3):266-274.PubMedArticle
54.
Jokiranta  E, Sourander  A, Suominen  A, Timonen-Soivio  L, Brown  AS, Sillanpää  M.  Epilepsy among children and adolescents with autism spectrum disorders: a population-based study.  J Autism Dev Disord. 2014;44(10):2547-2557.PubMedArticle
55.
Quintero  N, McIntyre  LL.  Sibling adjustment and maternal well-being: an examination of families with and without a child with an autism spectrum disorder.  Focus Autism Other Dev Disabl. 2010;25(1):37-46.PubMed
56.
Joelsson  P, Chudal  R, Gyllenberg  D,  et al.  Demographic characteristics and psychiatric comorbidity of children and adolescents diagnosed with ADHD in specialized healthcare [published online September 23, 2015].  Child Psychiatry Hum Dev. doi:10.1007/s10578-015-0591-6.PubMed
57.
Lampi  KM, Sourander  A, Gissler  M,  et al.  Brief report: validity of Finnish registry-based diagnoses of autism with the ADI-R.  Acta Paediatr. 2010;99(9):1425-1428.PubMedArticle
58.
Leivonen  S, Voutilainen  A, Hinkka-Yli-Salomäki  S,  et al.  A nationwide register study of the characteristics, incidence and validity of diagnosed Tourette syndrome and other tic disorders.  Acta Paediatr. 2014;103(9):984-990.PubMedArticle
59.
Sund  R.  Quality of the Finnish Hospital Discharge Register: a systematic review.  Scand J Public Health. 2012;40(6):505-515.PubMedArticle
60.
Sourander  A, Helstelä  L, Ristkari  T, Ikäheimo  K, Helenius  H, Piha  J.  Child and adolescent mental health service use in Finland.  Soc Psychiatry Psychiatr Epidemiol. 2001;36(6):294-298.PubMedArticle
61.
Sourander  A, Santalahti  P, Haavisto  A, Piha  J, IkÄheimo  K, Helenius  H.  Have there been changes in children’s psychiatric symptoms and mental health service use? a 10-year comparison from Finland.  J Am Acad Child Adolesc Psychiatry. 2004;43(9):1134-1145.PubMedArticle
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