The familial risk of autism

Abstract

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.

Figure 1

Age-cumulative probabilities for ASD diagnosis in sibling with and without a sibling with an earlier ASD diagnosis. 95% two-sided point wise confidence bands for exposed siblings. Dashed line: Cumulative probability of an autism diagnosis up to this age for siblings with a sibling proband with an autism diagnosis. Solid line: Cumulative probability of an autism diagnosis up to this age for siblings with a sibling proband free from an autism diagnosis.

Figure 2

ASD adjusted relative recurrence risks for full and maternal (MH) and paternal (PH) half siblings, cousins and DZ twins. Point estimates and two-sided 95% confidence intervals. MZ twins not shown. Male-Female indicate risk in female exposed to a male relative. The star for MZ twin indicate a truncated right confidence too wide to fit the figure. Adjusted: Models adjusting for birth cohort and sibling and proband sex and paternal and maternal psychiatric history at birth of the child and older maternal age (≤35, > 35) and older paternal age (≤40, > 40); MH: Maternal half siblings, PH: Paternal half siblings; Old Pa: Paternal age > 40; Yng Pa: Paternal age ≤40; Old Ma: Maternal age > 35; Yng Ma: Maternal age ≤35; Fa Psych; With a paternal psychiatric history; Fa Psych: With a paternal psychiatric history; With a maternal psychiatric history; Ma Psych: With a maternal psychiatric history; Parental psychiatric history was measured at birth of the first sibling in the family.

Figure 3

AD adjusted relative recurrence risks for full and maternal (MH) and paternal (PH) half siblings, cousins and DZ twins. Point estimates and two-sided 95% confidence intervals. MZ twins not shown. Male-Female indicate risk in female exposed to a male relative. The star for MZ twin indicate a truncated right confidence too wide to fit the figure. Adjusted: Models adjusting for birth cohort and sibling and proband sex and paternal and maternal psychiatric history at birth of the child and older maternal age (≤35, > 35) and older paternal age (≤40, > 40); MH: Maternal half siblings, PH: Paternal half siblings; Old Pa: Paternal age > 40; Yng Pa: Paternal age ≤40; Old Ma: Maternal age > 35; Yng Ma: Maternal age ≤35; Fa Psych; With a paternal psychiatric history; Fa Psych: With a paternal psychiatric history; With a maternal psychiatric history; Ma Psych: With a maternal psychiatric history; Parental psychiatric history was measured at birth of the first sibling in the family.