Influences of rare copy-number variation on human complex traits

Margaux L A Hujoel; Maxwell A Sherman; Alison R Barton; Ronen E Mukamel; Vijay G Sankaran; Chikashi Terao; Po-Ru Loh

doi:10.1016/j.cell.2022.09.028

Influences of rare copy-number variation on human complex traits

Cell. 2022 Oct 27;185(22):4233-4248.e27. doi: 10.1016/j.cell.2022.09.028.

Authors

Margaux L A Hujoel¹, Maxwell A Sherman², Alison R Barton³, Ronen E Mukamel⁴, Vijay G Sankaran⁵, Chikashi Terao⁶, Po-Ru Loh⁷

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: mhujoel@broadinstitute.org.
² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Bioinformatics and Integrative Genomics Program, Harvard Medical School, Boston, MA, USA.
⁴ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁶ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan; Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
⁷ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: poruloh@broadinstitute.org.

Abstract

The human genome contains hundreds of thousands of regions harboring copy-number variants (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs have been ascertainable from SNP-array data generated by large biobanks. We developed a computational approach leveraging haplotype sharing in biobank cohorts to more sensitively detect CNVs. Applied to UK Biobank, this approach accounted for approximately half of all rare gene inactivation events produced by genomic structural variation. This CNV call set enabled a detailed analysis of associations between CNVs and 56 quantitative traits, identifying 269 independent associations (p < 5 × 10^-8) likely to be causally driven by CNVs. Putative target genes were identifiable for nearly half of the loci, enabling insights into dosage sensitivity of these genes and uncovering several gene-trait relationships. These results demonstrate the ability of haplotype-informed analysis to provide insights into the genetic basis of human complex traits.

Keywords: Complex traits; Copy-number variants; Genetic associations; Haplotypes; Structural variation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations
Genome, Human
Humans
Multifactorial Inheritance*
Phenotype
Polymorphism, Single Nucleotide / genetics
Quantitative Trait Loci*

Abstract

Publication types

MeSH terms

Grants and funding