Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank

Abstract

Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ~ 0.001%) in exome sequencing data from 175,587 UK Biobank participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant (𝑃 < 1.68 × 10-7) and 17 nominally significant (𝑃 < 5.25 × 10-5) gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, includingFLG-asthma (𝑃 = 0.00205) andUSH2A-visual impairment (𝑃 = 0.0084). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.

Genetic Transformer: An Innovative Large Language Model Driven Approach for Rapid and Accurate Identification of Causative Variants in Rare Genetic Diseases

“…These contexts include (1) secondary findings, which are results that are not related to the indication for ordering the sequencing but that may nonetheless be of medical value or utility to the ordering physician and the patient. [25]; (2) other types of variations within coding regions, as well as those in other regions, such as copy number variations (CNVs), repeat expansions, and structural variations (SVs), which are anticipated to account for part of the remaining positive cases [26]; (3) compound loci situations, such as compound heterozygosity [27,28], complex compound patterns [29,30], and digenic inheritance [31,32]. However, these scenarios were not specifically trained for or evaluated in the current study and will be the focus of future model enhancements.…”