Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence phenotype. Genome-wide association (GWA) studies have identified >600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the utility of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P=0.016), and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented amongst variants that alter amino acid structure of proteins and expression levels of nearby genes. Our data explain ∼10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to ∼16% of phenotypic variation (∼20% of heritable variation). Although additional approaches are needed to fully dissect the genetic architecture of polygenic human traits, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10 −14 ), CDC123/CAMK1D (p=1.2×10 −10 ), TSPAN8/ LGR5 (p=1.1×10 −9 ), THADA (p=1.1×10 −9 ), ADAMTS9 (p=1.2×10 −8 ), and NOTCH2 (p=4.1×10 −8 ) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D.Genome-wide association studies are unbiased by previous hypotheses concerning candidate genes and pathways, but challenged by the modest effect sizes of individual common susceptibility variants and the need for stringent statistical thresholds. For example, the largest allelic odds ratio of any established common variant for T2D is ~1.35 (TCF7L2), with the nine other validated associations to common variants (excluding FTO, which has its primary effect through obesity) having allelic odds ratios between 1.1 and 1. 21-6,11,12. To augment power to detect additional loci of similar and/or smaller effect, we increased sample size by combining three previously published GWA studies (Diabetes Genetics Initiative [DGI], Finland-United States Investigation of NIDDM Genetics [FUSION], and Wellcome Trust Case Control Consortium [WTCCC])1-4, and extended SNP coverage by imputing untyped SNPs based on patterns of haplotype variation from the HapMap dataset13 (Table 1).We started with a set of genotyped autosomal SNPs that passed quality control (QC) filters in each study: in WTCCC, 393,143 SNPs from the Affymetrix 500k chip (MAF>0.01; 1,924 cases and 2,938 population-based controls from the Wellcome Trust Case Control Consortium3,4); in DGI, 378,860 Using these directly measured and imputed genotypes, we tested for association of each SNP with T2D in each study separately, corrected each study for residual population stratification, cryptic relatedness or technical artifacts using genomic control, and then combined these results in a genome-wide meta-analysis across a total of 10,128 samples (4,549 cases, 5,579 controls) (Methods; Supplementary Methods). We calculated that this sample size provides reasonable power to detect additional variants with properties similar to those previously identified by less formal data combination efforts1,2,4 (Supplementary Table 2). Unless otherwise indicated, results presented are derived from...
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes.
Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.
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