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Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence., Materials and Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction., Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10 -8 ). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure ( MARCO ) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 ( EDN1 ) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001)., Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 ( EDN1 ), associated with urgency incontinence, and macrophage receptor with collagenous structure ( MARCO ), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk., (© 2019 by the American Diabetes Association.)