UC San Diego

The genetic basis of autism is known to consist of de novo and inherited loss of function mutations in haploinsufficient genes. It is thought that inherited risk primarily derives from mothers, believed to be due to an increased tolerance for risk alleles. However, the distinct contributions of each parent to inherited risk for autism has not been explored in depth. We investigated paternal and maternal contributions to autism by analyzing the transmission of private deletions in coding and cis-regulatory (CRE-SVs) regions of functionally constrained genes in whole genomes of 10,015 individuals (2650 families). We then extended our transmission distortion analysis to encompass of loss of function single nucleotide variants (SNVs) and insertion/deletion (INDELs), as well as private potentially pathogenic missense mutations. Our goal is to untangle distinct modes of inheritance for autism risk, hypothesizing that fathers and mothers carry distinct risk contributions. We report that mothers and fathers over-transmit loss of function variants within functionally constrained coding regions. However, fathers but not mothers tended to over-transmit damaging CRE-SVs and missense variants to affected offspring. When we test the segregation of loss of function variants stratified by sex of the offspring, we find that most of the genetic risk to sons is derived from the father, which is not consistent with the previous female protective effect model. Our work demonstrates that inherited damaging variants comprise a significant component of missing heritability for autism with fathers contributing a substantial amount of risk.