A shared genetic susceptibility underlies diabetes, adiposity, and kidney phenotypes, yet few studies have leveraged this common genetic architecture in an attempt to clarify molecular functions, identify mechanistic common denominators, and prioritize variants for functional interrogation. We systematically interrogated evidence of a shared genetic architecture across adiposity (BMI [N=90,813], waist circumference[N=68,389], and waist to hip ratio [WHR, N=63,747]), type 2 diabetes (T2D, [N=98,686, Ncase=26,440], fasting glucose [FG, N=52,211], HbA1c [N=23,357], and fasting insulin [FI, N=48,395]), and kidney (eGFR [N=52,555] and chronic kidney disease [CKD, N=91,382, Ncase=10,883]) phenotypes in an ancestrally diverse study population (28% African American, 31% European ancestry, 28% Hispanic; 69% female; average age 56.9 (range 18-90)) within PAGE. We conducted a cross-trait meta-analysis using Adaptive Sum of Powered Score Tests (aSPU). We have identified 42 loci associated across these traits, (P<5e-8), including one preliminary novel cross-trait association for rs200812701, a nonsynonymous variant in KIF4B p.Ala491Valthat was associated with BMI, waist circumference, and HbA1c. rs200812701 is rare (minor allele frequency [MAF]<0.1%) in all populations except Native Hawaiians (MAF=25%) and Asians (MAF=8%). Many of these loci are known for one trait, but the identification of shared genetic susceptibility for these loci is novel. For example, the PEPD locus is established for adiposity measures, namely WHR; however, this cross-trait association is driven more so by FI, T2D and eGFR. Our systematic interrogation of the shared genetic susceptibility underlying diabetes, adiposity, and kidney traits in an ancestrally diverse population has revealed novel loci and evidence of molecular functions and mechanistic common denominators underlying GWAS findings, demonstrating the utility of our approach.
H.M. Highland: None. C. Downie: None. S.F. Dimos: None. M. Graff: None. L.M. Polfus: None. B.F. Darst: None. A.R.M. Baldassari: None. C. Sitlani: None. A. Howard: None. C.L. Kooperberg: None. R. Loos: None. T. Matise: None. A.K. Mottl: None. K.E. North: None. C.L. Avery: Research Support; Self; Amgen.
American Diabetes Association (1-19-PDF-045 to H.M.M.); National Institutes of Health (T32HL007055, T32HL129982, R01HL142825)