28 research outputs found
The trans-ancestral genomic architecture of glycemic traits
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe
Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p
Recommended from our members
An examination of Anglo and Latino parenting practices: relation to behavior problems in children with or without developmental delay.
The transactional model of development has received empirical support in research on at-risk children. However, little is known about the role of ethnicity or child delay status (i.e., developmental delay [DD] or typical cognitive development [TD]) in the process of parents adapting to their child's behavior problems and special needs. We examined whether Latina (N=44) and Anglo (N=147) mothers of 3-year-old children with or without DD differed in their use of two parenting practices, maternal scaffolding and sensitivity. We also examined how the status and ethnic groups differed in child behavior problems at ages 3 and 5 and whether parenting predicted change in behavior problems over time in the ethnic and status groups. Analyses generally supported previous research on status group differences in behavior problems (DD higher) and parenting practices (TD higher). Parenting practices predicted a decrease in externalizing problems from child age 3 to 5 years among Latino families only. Child developmental status was not associated with change in behavior problems. Cultural perspectives on the transactional model of development and implications for intervention are discussed
Developmental delay and emotion dysregulation: Predicting parent-child conflict across early to middle childhood.
Cumulative risk research has increased understanding of how multiple risk factors impact various socioemotional and interpersonal outcomes across the life span. However, little is known about risk factors for parent-child conflict early in development, where identifying predictors of change could be highly salient for intervention. Given their established association with parent-child conflict, child developmental delay (DD) and emotion dysregulation were examined as predictors of change in conflict across early to middle childhood (ages 3 to 7 years). Participants (n = 211) were part of a longitudinal study examining the development of psychopathology in children with or without DD. Level of parent-child conflict was derived from naturalistic home observations, whereas child dysregulation was measured using an adapted CBCL-Emotion Dysregulation Index. PROCESS was used to examine the conditional interactive effects of delay status (typically developing, DD) and dysregulation on change in conflict from child ages 3 to 5 and 5 to 7 years. Across both of these timeframes, parent-child conflict increased only for families of children with both DD and high dysregulation, providing support for an interactive risk model of parent-child conflict. Findings are considered in the context of developmental transitions, and implications for intervention are discussed. (PsycINFO Database Recor
Recommended from our members
Developmental delay and emotion dysregulation: Predicting parent-child conflict across early to middle childhood.
Cumulative risk research has increased understanding of how multiple risk factors impact various socioemotional and interpersonal outcomes across the life span. However, little is known about risk factors for parent-child conflict early in development, where identifying predictors of change could be highly salient for intervention. Given their established association with parent-child conflict, child developmental delay (DD) and emotion dysregulation were examined as predictors of change in conflict across early to middle childhood (ages 3 to 7 years). Participants (n = 211) were part of a longitudinal study examining the development of psychopathology in children with or without DD. Level of parent-child conflict was derived from naturalistic home observations, whereas child dysregulation was measured using an adapted CBCL-Emotion Dysregulation Index. PROCESS was used to examine the conditional interactive effects of delay status (typically developing, DD) and dysregulation on change in conflict from child ages 3 to 5 and 5 to 7 years. Across both of these timeframes, parent-child conflict increased only for families of children with both DD and high dysregulation, providing support for an interactive risk model of parent-child conflict. Findings are considered in the context of developmental transitions, and implications for intervention are discussed. (PsycINFO Database Recor