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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants T32GM102057 to Miss Corrine Smolen and NS122398 and GM121907 to Dr. Santhosh Girirajan from the National Institutes of Health. Dr. Charles Schwartz was supported, in part, by a grant from the South Carolina Department of Disabilities and Special Needs. Dr. Corrado Romano was supported by the Italian Ministry of Health-Ricerca Corrente 2022. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Families provided informed consent to give blood samples and phenotypic data under Pennsylvania State University Institutional Review Board approved protocol #STUDY00000278, and deidentified data from medical reports were collected under approved protocol #STUDY00017269.The study of this cohort was conducted under an IRB protocol approved by the Western Institutional Review Board (IRB #STUDY 1169768, WIRB Pro Number 20162523), which states that this research meets the requirements for a waiver of consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at NCBI dbGaP study accession phs00245. All code for analysis will be available at GitHub (https://github.com/girirajanlab/Assortative\_mating\_project).