Measuring shared variants in cohorts of discordant siblings with applications to autism.

Proc Natl Acad Sci U S A 2017 07 19;114(27):7073-7076. Epub 2017 Jun 19.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS ( value ∼ 0.00001). Fathers in multiplex families have marginally greater similarity ( value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender.

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http://dx.doi.org/10.1073/pnas.1700439114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502605PMC
July 2017
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