Assortative mating and parental genetic relatedness drive the pathogenicity of variably expressive variants

Abstract

We examined more than 38,000 spouse pairs from four neurodevelopmental disease cohorts and the UK Biobank to identify phenotypic and genetic patterns in parents associated with neurodevelopmental disease risk in children. We identified correlations between six phenotypes in parents and children, including correlations of clinical diagnoses such as obsessive-compulsive disorder (R=0.31-0.49, p<0.001), and two measures of sub-clinical autism features in parents affecting several autism severity measures in children, such as bi-parental mean Social Responsiveness Scale (SRS) scores affecting proband SRS scores (regression coefficient=0.11, p=0.003). We further describe patterns of phenotypic and genetic similarity between spouses, where spouses show both within- and cross- disorder correlations for seven neurological and psychiatric phenotypes, including a within-disorder correlation for depression (R=0.25-0.72, p<0.001) and a cross-disorder correlation between schizophrenia and personality disorder (R=0.20-0.57, p<0.001). Further, these spouses with similar phenotypes were significantly correlated for rare variant burden (R=0.07-0.57, p<0.0001). We propose that assortative mating on these features may drive the increases in genetic risk over generations and the appearance of "genetic anticipation" associated with many variably expressive variants. We further identified parental relatedness as a risk factor for neurodevelopmental disorders through its inverse correlations with burden and pathogenicity of rare variants and propose that parental relatedness drives disease risk by increasing genome-wide homozygosity in children (R=0.09-0.30, p<0.001). Our results highlight the utility of assessing parent phenotypes and genotypes in predicting features in children carrying variably expressive variants and counseling families carrying these variants.

Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions

“…Parental assortment is known to be particularly strong for educational attainment and cognitive ability, with estimates of phenotypic correlation between spouses ranging from 0.25 to 0.6 57–64 . It is also observed for psychiatric conditions 63,65–67 , including in parents of autistic individuals and of individuals with neurodevelopmental conditions due to the 16p12.1 deletion 68 . One consequence of parental assortment is that it induces a correlation between alleles that act in the same direction on a trait, both between parents and, in their descendents, within and between loci 57 .…”

“…Thus, parental assortment on cognitive ability or correlated traits (e.g. educational attainment) would be expected to lead to individuals with inherited rare variants associated with reduced cognitive ability 8,9,12,69 also having a polygenic background of common variants associated with reduced cognitive ability 57,68 . In the context of our polygenic score analyses in Figure 4 , in the proband-only model, the proband’s polygenic score would statistically capture (‘tag’) the correlated effects of these rare variants (which causally impact neurodevelopmental conditions 69,70 ).…”