| Title: | Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank |
| Journal: | Cell Genomics |
| Published: | 28 Jun 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/38944039/ |
| DOI: | https://doi.org/10.1016/j.xgen.2024.100602 |
| Citations: | 1 (1 in last 2 years) as of 8 Aug 2024 |
Publication 11774
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Abstract
The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10-7) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10-8). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.</p>
14 Keywords
- Asthma
- Biological Specimen Banks
- Exome
- Female
- Filaggrin Proteins
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Heterozygote
- Humans
- Male
- Phenotype
- Pulmonary Disease, Chronic Obstructive
- UK Biobank
- United Kingdom
11 Authors
- Frederik H. Lassen
- Samvida S. Venkatesh
- Nikolas Baya
- Barney Hill
- Wei Zhou
- Alex Bloemendal
- Benjamin M. Neale
- Benedikt M. Kessler
- Nicola Whiffin
- Cecilia M. Lindgren
- Duncan S. Palmer
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