Vertical Transmission of Autism Spectrum Disorder. N. Risch1,2, L. Shen2, Y. Qian3, M. Massolo3, L. Croen2,3 1) Institute for Human Genetics, UCSF, San Francisco, CA., USA; 2) Research Program on Genes, Environment and Health, Kaiser Permanente Division of Research, Oakland, CA, USA; 3) Autism Research Program, Kaiser Permanente Division of Research, Oakland, CA, USA.
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a complex pattern of inheritance. Twin and family studies have consistently provided evidence of a genetic contribution through an elevated concordance in MZ versus DZ twins, and higher recurrence risks for full sibs compared to maternal half sibs. However, an elevated recurrence risk to maternal versus paternal half-sibs, a significant birth order effect, and increasing risk with short inter-birth interval also suggest maternal effects. It has generally been assumed that individuals with ASD rarely if ever reproduce. Thus, no studies of risk to the children of parents with ASD have been reported. Here we report results from the first such study. It is based on the Kaiser Permanente Northern California (KPNC) Family Linkage Database (KPFLD). All KPNC members age 26 or less born prior to 2009 were linked to state of California birth certificates to identify parents. Parent information was then matched to the KPNC adult membership to identify nuclear families. In total, approximately 500,000 families were identified to form the KPFLD. The KPFLD was then linked to the KPNC ASD registry, which maintains records on all individuals in KPNC with a presumptive diagnosis of ASD. The linkage of the KPFLD with the ASD registry identified 225 nuclear families with an ASD affected mother, 172 families with an ASD affected father, and 37 families with both an ASD affected mother and father (dual matings). The risk to children of affected mothers was observed to be 31.7% (155 affected out of 489 total children); the risk to children of affected fathers was somewhat lower at 25.1% (80 affected out of 319 total children). The risk to children of dual matings was 46.8% (37 affected out of 79 total children). We also noted a birth order effect in children of affected mothers. In the children of affected mothers and unaffected fathers, the risks were 36.4%, 29.1% and 25.5% to first-born, second-born and later-born children, respectively. For dual matings, the risks were 67.6%, 34.5% and 15.4% to first-born, second-born and later-born children, respectively. By contrast, the recurrence risk to full sibs of ASD children was 11.4% (370 affected out of 3243). The remarkably high risk to children of affected parents demonstrates the vertical transmissibility of ASD, and the birth order effects again emphasize the potential role of maternal environment in modulating genetic risks.
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