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.

Figure 1.. Parental phenotypes predict clinical outcomes in children.

(A) Tetrachoric correlations between self-reported psychiatric disorders in mothers and fathers and male and female probands within the SPARK autism cohort (n=592-4,757 for each correlation). (B) Regression coefficients from linear models incorporating effects of both genetic factors and parental phenotypes towards quantitative proband autism and cognitive phenotypes (n= 1,628-2,168 for each model). RBS: Repetitive Behaviors Scale, SRS: Social Responsiveness Scale, CBCL int: Child Behavior Checklist 6-18 internalizing, FSIQ: Full-scale IQ. Selected models shown here, full data in Table S4. Blue dots and lines indicate significance after Bonferroni-correction. * Bonferroni-corrected p≤0.05, ** p≤0.01, *** p≤0.001.

Figure 2.. Patterns of assortative mating in multiple cohorts.

(A) Percentage of carrier and non-carrier spouses in a cohort of 16p12.1 deletion carrier families with five neurological and psychiatric disorders (n=49-52). (B-D) Tetrachoric correlations of neurological and psychiatric phenotypes between (B) carrier and non-carrier spouses in the 16p12.1 deletion cohort (n=28-50), (C) mothers and fathers in the SPARK autism cohort (n=3,956-6,142), and (D) female and male spousal partners in the UK Biobank (n=19,468-22,953). Grey boxes indicate insufficient sample size for correlation. * Bonferroni-corrected p≤0.05, ** p≤0.01, *** p≤0.001.

Figure 3.. Assortative mating drives increases in genetic risk variance.

(A) Pearson correlations of rare, likely deleterious SNVs in female and male partners of spouse pairs from the 16p12.1 deletion cohort (n=59), SPARK (n=7,352) and SSC (n=2,397) autism, and the UK Biobank (n=10,323) cohorts. (B) Schematic illustrating increases in disease liability variance over generations resulting from assortative mating. (C) Example pedigree of assortative mating and compounding disease severity in a 16p12.1 deletion carrier family. White indicates no overt phenotype.

Figure 4.. Parental relatedness correlates with homozygosity in children.

Pearson correlations of parental relatedness (measured as kinship coefficients) and the number of large (≥1 Mb) runs of homozygosity male and female probands in the SSC (male n=1,711, female n=270) and SPARK (male n=2,956, female n=758) autism cohorts.

Figure 5.. Parental relatedness is a risk factor for neurodevelopmental disorders.

(A) Pearson correlations of the average burden of rare, likely deleterious variants and relatedness (measured as kinship coefficients) in spouse pairs from the 16p12.1 deletion (n=44), SPARK (n=4,095) and SSC (n=1,813) autism, and UK Biobank (n=6,315) cohorts. (B) Comparison of parental relatedness among SSC probands with loss-of-function mutations in Tier S SFARI genes (n=102) and without mutations in SFARI genes (n=1,243). Lines indicate median. One tailed t-test. (C-E) Comparisons of parental relatedness among probands ascertained for neurodevelopmental disease with (C) de novo (n=129) and inherited (n=116) CNVs, (D) deletions (n=249) and duplications (n=97), and (E) syndromic (n=47) and variably expressive (n=299) CNVs. Lines indicate median. One tailed t-test.