GWAS for the composite traits of hematuria and albuminuria.

Our GWAS of hematuria in the UK Biobank identified 6 loci, some of which overlap with loci for albuminuria suggesting pleiotropy. Since clinical syndromes are often defined by combinations of traits, generating a combined phenotype can improve power to detect loci influencing multiple characteristics. Thus the composite trait of hematuria and albuminuria was chosen to enrich for glomerular pathologies. Cases had both hematuria defined by ICD codes and albuminuria defined as uACR > 3 mg/mmol. Controls had neither an ICD code for hematuria nor an uACR > 3 mg/mmol. 2429 cases and 343,509 controls from the UK Biobank were included. eGFR was lower in cases compared to controls, with the exception of the comparison in females using CKD-EPI after age adjustment. Variants at 4 loci met genome-wide significance with the following nearest genes: COL4A4, TRIM27, ETV1 and CUBN. TRIM27 is part of the extended MHC locus. All loci with the exception of ETV1 were replicated in the Geisinger MyCode cohort. The previous GWAS of hematuria reported COL4A3-COL4A4 variants and HLA-B*0801 within MHC, which is in linkage disequilibrium with the TRIM27 variant (D' = 0.59). TRIM27 is highly expressed in the tubules. Additional loci included a coding sequence variant in CUBN (p.Ala2914Val, MAF = 0.014 (A), p = 3.29E-8, OR = 2.09, 95% CI = 1.61-2.72). Overall, GWAS for the composite trait of hematuria and albuminuria identified 4 loci, 2 of which were not previously identified in a GWAS of hematuria.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.