Three linked variants have opposing regulatory effects on isovaleryl-CoA dehydrogenase gene expression.

Document Type

Article

Publication Date

1-20-2024

Keywords

Humans, Isovaleryl-CoA Dehydrogenase, Oxidoreductases, Oxidoreductases Acting on CH-CH Group Donors, Genome-Wide Association Study, Gene Expression

JAX Source

Hum Mol Genet. 2024;33(3):270-83.

ISSN

1460-2083

PMID

37930192

DOI

https://doi.org/10.1093/hmg/ddad177

Grant

We acknowledge funding from the Howard Hughes Medical Insti- tute and the National Institute of Health grants DP2OD006514 to P.C.S. and K99HG008179 to R.S.T. The Cora Du Bois fellowship supported E.A.B.

Abstract

While genome-wide association studies (GWAS) and positive selection scans identify genomic loci driving human phenotypic diversity, functional validation is required to discover the variant(s) responsible. We dissected the IVD gene locus-which encodes the isovaleryl-CoA dehydrogenase enzyme-implicated by selection statistics, multiple GWAS, and clinical genetics as important to function and fitness. We combined luciferase assays, CRISPR/Cas9 genome-editing, massively parallel reporter assays (MPRA), and a deletion tiling MPRA strategy across regulatory loci. We identified three regulatory variants, including an indel, that may underpin GWAS signals for pulmonary fibrosis and testosterone, and that are linked on a positively selected haplotype in the Japanese population. These regulatory variants exhibit synergistic and opposing effects on IVD expression experimentally. Alleles at these variants lie on a haplotype tagged by the variant most strongly associated with IVD expression and metabolites, but with no functional evidence itself. This work demonstrates how comprehensive functional investigation and multiple technologies are needed to discover the true genetic drivers of phenotypic diversity.

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