Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

Udler, Miriam S.; Kim, Jaegil; Grotthuss, Marcin von; Bonàs-Guarch, Sílvia; Cole, Joanne B.; Chiou, Joshua; Boehnke, Michael; Laakso, Markku; Atzmon, Gil; Gläser, Benjamin; Mercader, Josep M.; Gaulton, Kyle J.; Flannick, Jason; Getz, Gad; Florez, José C.

doi:10.1371/journal.pmed.1002654

Cited by 403 publications

(502 citation statements)

References 74 publications

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“…To gauge if these transcribed elements could be relevant for diverse disease/traits, we computed enrichment for islet TCs to overlap GWAS loci for 116 traits from the NHGRI catalog (Buniello et al 2019) and other relevant studies (Udler et al 2018). We observed that traits such as Fasting Glucose (FGlu) (fold enrichment = 7.05, P value = 3.30x10 -4 ), metabolic traits (fold enrichment = 6.46, P value = 2.03x10 -4 ) were among the most highly enriched, highlighting the relevance of these transcribed elements for islet biology ( Figure. 1F, Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Because T2D is orchestrated through a complex interplay between islet beta cell dysfunction and insulin resistance in peripheral tissues, we reasoned that some underlying pathways in T2D might be more relevant in islets than others. To explore this rationale, we utilized results from a previous study that analyzed GWAS data for T2D along with 47 other diabetes related traits and identified clusters of T2D GWAS signals (Udler et al 2018). Interestingly, we observe that GWAS loci in the islet beta cell and proinsulin cluster were highly enriched to overlap islet TCs (fold enrichment = 5.62, P value = 0.004), whereas loci in the insulin resistance cluster were depleted (fold enrichment = 0.97; Figure 1F, Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

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A transcription start site map in human pancreatic islets reveals functional regulatory signatures

Varshney

Kyono

Elangovan

et al. 2019

Preprint

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Identifying active regulatory elements and their molecular signatures is critical to understand gene regulatory mechanisms and subsequently better delineating biological mechanisms of complex diseases and traits. Studies have shown that active enhancers can be transcribed into enhancer RNA (eRNA). Here, we identify actively transcribed regulatory elements in human pancreatic islets by generating eRNA profiles using cap analysis of gene expression (CAGE) across 70 islet samples. We identify 9,954 clusters of CAGE tag transcription start sites (TSS) or tag clusters (TCs) in islets, ~20% of which are islet-specific when compared to CAGE TCs across publicly available tissues. Islet TCs are most enriched to overlap genome wide association study (GWAS) loci for islet-relevant traits such as fasting glucose. We integrated islet CAGE profiles with diverse epigenomic information such as chromatin immunoprecipitation followed by sequencing (ChIP-seq) profiles of five histone modifications and accessible chromatin profiles from the assay for transposase accessible chromatin followed by sequencing (ATAC-seq), to understand how the underlying islet chromatin landscape is associated with TSSs. We identify that ATAC-seq informed transcription factor (TF) binding sites (TF 'footprint' motifs) for the RFX TF family are highly enriched in transcribed regions occurring in enhancer chromatin states, whereas TF footprint motifs for the ETS family are highly enriched in transcribed regions within promoter chromatin states. Using massively parallel reporter assays in a rat pancreatic islet beta cell line, we tested the activity of 3,378 islet CAGE elements and found that 2,279 (~67.5%) show significant regulatory activity (5% FDR). We find that TCs within accessible enhancer show higher enrichment to overlap T2D GWAS loci than accessible enhancer annotations alone, suggesting that TC annotations pinpoint active regions within the enhancer chromatin states. This work provides a high-resolution transcriptional regulatory map of human pancreatic islets.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A transcription start site map in human pancreatic islets reveals functional regulatory signatures

Varshney

Kyono

Elangovan

et al. 2019

Preprint

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“…For example, the top and bottom 2.5% of the distribution differ in risk of diabetes by ~ 10‐fold. These 400 variants can be grouped together according to the pathophysiological process they affect into what have been termed process‐specific polygenic risk scores, e.g., those affecting beta‐cell function, or fat distribution . These have modest effects on the underlying trait, and as diabetes drugs act on these particular traits, one would hope that these process‐specific polygenic risk scores will have moderate impact on glycemic response to diabetes drugs.…”

Section: Future Studies Of Pharmacogenetics In Diabetesmentioning

confidence: 99%

Diabetes: Is There a Future for Pharmacogenomics Guided Treatment?

Pearson

2019

Clin Pharma and Therapeutics

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Diabetes is a disease defined on the basis of hyperglycemia. There are monogenic forms of diabetes where defining the genetic cause has a dramatic impact on treatment—with patients being able to transition from insulin to sulfonylureas. However, the majority of diabetes is type 2 diabetes. This review outlines the robust evidence accrued to date for pharmacogenetics of metformin, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase‐4 inhibitors but highlights that these variants will only be of clinical utility when the genotype is already known at the point of prescribing. The future of pharmacogenetics in diabetes and other common complex disease relies on a paradigm shift—that of preemptive panel genotyping and use of clinical decision support tools to assimilate this genetic information with other clinical phenotypic data and to present this information simply to the prescriber. Given the recent dramatic fall in genotyping costs, this future is not far off.

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“…Often defined according to arbitrary diagnostic criteria, complex 65 diseases can represent the phenotypic convergence of numerous genetic etiologies (4)(5)(6)(7)(8). 66Recent studies in type 2 diabetes support the concept that there are disease subtypes with 67 distinct genetic architecture (7,8). Identifying and addressing genetic heterogeneity in 68 complex diseases could increase power to detect causal variants and improve treatment 69 efficacy (9).…”

mentioning

confidence: 99%

“…Understanding the genetic architecture of complex diseases is a central challenge in 64 human genetics (1-3). Often defined according to arbitrary diagnostic criteria, complex 65 diseases can represent the phenotypic convergence of numerous genetic etiologies (4)(5)(6)(7)(8). 66…”

mentioning

confidence: 99%

Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

Dapas¹,

Lin²,

Nadkarni

et al. 2019

Preprint

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AD) 20 ghayes@northwestern.edu (MGH) 21 22 DISCLOSURE STATEMENT: The authors have nothing to disclose. 23 metabolic subtype (KCNH7/FIGN, P=1.0×10 -8 ). We have previously reported that rare 47 variants in DENND1A, a gene regulating androgen biosynthesis, were associated with PCOS 48 quantitative traits in a family-based whole genome sequencing analysis. We classified the 49 reproductive and metabolic subtypes in this family-based PCOS cohort and found that the 50 subtypes tended to cluster in families and that carriers of rare DENND1A variants were 51 significantly more likely to have the reproductive subtype of PCOS. Limitations of our study 52 were that only PCOS cases of European ancestry diagnosed by NIH criteria were included, 53 the sample sizes for the subtype GWAS were small, and the GWAS findings were not 54 replicated. 55 56 Conclusions 57In conclusion, we have found stable reproductive and metabolic subtypes of PCOS. Further, 58 these subtypes were associated with novel susceptibility loci. Our results suggest that these 59 subtypes are biologically relevant since they have distinct genetic architectures. This study 60 demonstrates how precise phenotypic delineation can be more powerful than increases in 61 sample size for genetic association studies. 62 63Understanding the genetic architecture of complex diseases is a central challenge in 64 human genetics (1-3). Often defined according to arbitrary diagnostic criteria, complex 65 diseases can represent the phenotypic convergence of numerous genetic etiologies (4)(5)(6)(7)(8). 66Recent studies in type 2 diabetes support the concept that there are disease subtypes with 67 distinct genetic architecture (7,8). Identifying and addressing genetic heterogeneity in 68 complex diseases could increase power to detect causal variants and improve treatment 69 efficacy (9). 70Polycystic ovary syndrome (PCOS) is a highly heritable, complex genetic disorder 71 affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic 72 criteria applied (10). It is characterized by a variable constellation of reproductive and 73 metabolic abnormalities (Fig 1). It is the leading cause of anovulatory infertility and a major 74 risk factor for type 2 diabetes (T2D) in women (11). Despite these substantial morbidities, 75 the etiology(ies) of PCOS remains unknown (12). Accordingly, the commonly-used 76 diagnostic criteria for PCOS, the National Institutes of Health (NIH) criteria (13) and the 77 Rotterdam criteria (14,15), are based on expert opinion, rather than mechanistic insights, and 78 are designed to account for the diverse phenotypic presentations of PCOS. The NIH criteria 79 require the presence of hyperandrogenism (HA) and chronic oligo/anovulation or ovarian 80 dysfunction (OD) (13). The Rotterdam criteria include polycystic ovarian morphology 81 (PCOM) and require the presence of at least two of these three key reproductive traits, 82 resulting in three different affected phenotypes: HA and OD with or without PCOM, also 83 known as NIH PCOS, as w...

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Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

Cited by 403 publications

References 74 publications

A transcription start site map in human pancreatic islets reveals functional regulatory signatures

A transcription start site map in human pancreatic islets reveals functional regulatory signatures

Diabetes: Is There a Future for Pharmacogenomics Guided Treatment?

Phenotypic clustering reveals distinct subtypes of polycystic ovary syndrome with novel genetic associations

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