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Original Investigation |

The Familial Risk of Autism

Sven Sandin, MSc1,2; Paul Lichtenstein, PhD1; Ralf Kuja-Halkola, MSc1; Henrik Larsson, PhD1; Christina M. Hultman, PhD1; Abraham Reichenberg, PhD3,4,5
[+] Author Affiliations
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden
2Department of Psychosis Studies, Institute of Psychiatry, King’s College London, United Kingdom
3Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, New York
4Department of Preventive Medicine, Ichan School of Medicine at Mount Sinai, New York, New York
5Seaver Autism Center and Friedman Brain Institute, Ichan School of Medicine at Mount Sinai, New York, New York
JAMA. 2014;311(17):1770-1777. doi:10.1001/jama.2014.4144.
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Importance  Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved.

Objective  To provide estimates of familial aggregation and heritability of ASD.

Design, Setting, and Participants  A population-based cohort including 2 049 973 Swedish children born 1982 through 2006. We identified 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs, and 5 799 875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained.

Main Outcomes and Measures  The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors.

Results  In the sample, 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100 000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64).

Conclusions and Relevance  Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

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Figure 1.
Age-Cumulative Probabilities for ASD Diagnosis in Siblings With a Full Sibling With ASD and in Siblings With a Full Sibling Without an ASD Diagnosis

ASD indicates autism spectrum disorder. Shaded areas represent 95% 2-sided point-wise confidence interval bands. The siblings who had a full-sibling with ASD were followed for 76 481 person-years resulting in 634 ASD events. The siblings who had a full sibling without ASD were followed for 35 486 922 person-years resulting in 17 327 ASD events.

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Figure 2.
Adjusted Relative Recurrence Risks for Autism Spectrum Disorder Among Full and Maternal and Paternal Half Siblings, Cousins, and Monozygotic and Dizygotic Twins

ASD indicates autism spectrum disorder; RRR, relative recurrence risk. Point estimates and 2-sided 95% CIs. Rate indicates the number of autism spectrum disorder cases per 100 000 person-years for participants exposed and unexposed for sibling autism spectrum disorder; person-year, the sum of years of follow-up for participants exposed and unexposed for sibling autism spectrum disorder. Model is adjusted for 5-year birth cohorts, sex, parental age, and parental psychiatric history.

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Place holder to copy figure label and caption
Figure 3.
Adjusted Relative Recurrence Risks for Autistic Disorder Among Full and Maternal and Paternal Half Siblings, Cousins, and Monozygotic and Dizygotic Twins.

RRR indicates relative recurrence risk. Point estimates and 2-sided 95% CIs. Rate indicates the number of autistic disorder cases per 100 000 person-years for participants exposed and unexposed for sibling autistic disorder; person-year, the sum of years of follow-up for participants exposed and unexposed for sibling autistic disorder. Model is adjusted for 5-year birth cohorts, sex, parental age, and parental psychiatric history.

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