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

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

doi:10.1016/j.xgen.2024.100602

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

Cell Genom. 2024 Jul 10;4(7):100602. doi: 10.1016/j.xgen.2024.100602. Epub 2024 Jun 28.

Authors

Affiliations

¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. Electronic address: flassen@well.ox.ac.uk.
² Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
³ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Novo Nordisk Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK. Electronic address: cecilia.lindgren@wrh.ox.ac.uk.
⁹ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK. Electronic address: duncan.stuart.palmer@gmail.com.

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.

Keywords: bi-allelic; compound heterozygosity; longtudinal; phasing; population genetics; recessive.

MeSH terms

Asthma / genetics
Biological Specimen Banks*
Exome* / genetics
Female
Filaggrin Proteins
Genetic Predisposition to Disease
Genome-Wide Association Study
Heterozygote*
Humans
Male
Phenotype*
Pulmonary Disease, Chronic Obstructive / genetics
UK Biobank
United Kingdom / epidemiology

Substances

Filaggrin Proteins

Abstract

MeSH terms

Substances

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