biostudies-literatureZhang YNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney Diseasese184140https://www.ebi.ac.uk/biostudies/studies/S-EPMC11790016biostudies-literatureUnknown10(2)Mechanisms underpinning signals from genome-wide association studies remain poorly understood, particularly for noncoding variation and for complex diseases such as type 2 diabetes mellitus (T2D) where pathogenic mechanisms in multiple different tissues may be disease driving. One approach is to study relevant endophenotypes, a strategy we applied to the UBE2E2 locus where noncoding single nucleotide variants (SNVs) are associated with both T2D and visceral adiposity (a pathologic endophenotype). We integrated CRISPR targeting of SNV-containing regions and unbiased CRISPR interference (CRISPRi) screening to establish candidate cis-regulatory regions, complemented by genetic loss of function in murine diet-induced obesity or ex vivo adipogenesis assays. Nomination of a single causal gene waJCI insightNoncoding variation near UBE2E2 orchestrates cardiometabolic pathophenotypes through polygenic effectors.PMC11790016R01DK120659T32 DK007052R01 DK120659Steinhauser MLYang JPesaresi TSharma AXAndrews REKumar GVNChen HLiu SQiao WAmorim TZhang YDavid NLPatel KfalseNoncoding variation near UBE2E2 orchestrates cardiometabolic pathophenotypes through polygenic effectors.Mechanisms underpinning signals from genome-wide association studies remain poorly understood, particularly for noncoding variation and for complex diseases such as type 2 diabetes mellitus (T2D) where pathogenic mechanisms in multiple different tissues may be disease driving. One approach is to study relevant endophenotypes, a strategy we applied to the UBE2E2 locus where noncoding single nucleotide variants (SNVs) are associated with both T2D and visceral adiposity (a pathologic endophenotype). We integrated CRISPR targeting of SNV-containing regions and unbiased CRISPR interference (CRISPRi) screening to establish candidate cis-regulatory regions, complemented by genetic loss of function in murine diet-induced obesity or ex vivo adipogenesis assays. Nomination of a single causal gene wa2024-01-01T00:00:00Z2024 Dec2026-06-02T04:23:55.076Z2025-04-19T16:23:54.499ZS-EPMC117900163965653810.1172/jci.insight.184140