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1.
Diabetes ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439647

RESUMO

Disruption of the adaptor protein SH2B1 is associated with severe obesity, insulin resistance and neurobehavioral abnormalities in mice and humans. Here we identify 15 SH2B1 mutations in severely obese children. Four obesity-associated human SH2B1 mutations lie in the Pleckstrin Homology (PH) domain, suggesting that the PH domain is essential for SH2B1's function. We generated a mouse model of a human variant in this domain (P322S). P322S/P332S mice exhibited substantial prenatal lethality. Examination of the P322S/+ metabolic phenotype revealed late-onset glucose intolerance. To circumvent P322S/P322S lethality, mice containing a 2-amino acid deletion within the SH2B1 PH domain (ΔP317, R318; ΔPR) were studied. Mice homozygous for ΔPR were born at the expected Mendelian ratio and exhibited obesity plus insulin resistance and glucose intolerance beyond that attributable to their increased adiposity. These studies demonstrate that the PH domain plays a crucial role in SH2B1 control of energy balance and glucose homeostasis.

2.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

3.
Nat Rev Genet ; 20(9): 562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270439

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Nat Rev Genet ; 20(9): 520-535, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31235872

RESUMO

Risk of disease is multifactorial and can be shaped by socio-economic, demographic, cultural, environmental and genetic factors. Our understanding of the genetic determinants of disease risk has greatly advanced with the advent of genome-wide association studies (GWAS), which detect associations between genetic variants and complex traits or diseases by comparing populations of cases and controls. However, much of this discovery has occurred through GWAS of individuals of European ancestry, with limited representation of other populations, including from Africa, The Americas, Asia and Oceania. Population demography, genetic drift and adaptation to environments over thousands of years have led globally to the diversification of populations. This global genomic diversity can provide new opportunities for discovery and translation into therapies, as well as a better understanding of population disease risk. Large-scale multi-ethnic and representative biobanks and population health resources provide unprecedented opportunities to understand the genetic determinants of disease on a global scale.

6.
Diabetologia ; 62(7): 1204-1211, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31049640

RESUMO

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations. METHODS: We conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches. RESULTS: The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10-13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10-9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations. CONCLUSIONS/INTERPRETATION: These results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes.

7.
Am J Hum Genet ; 104(5): 985-989, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31006513

RESUMO

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

8.
Cell ; 177(1): 146-161, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901536

RESUMO

Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.

9.
Am J Clin Nutr ; 109(2): 276-287, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721968

RESUMO

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

10.
Cell ; 176(4): 729-742.e18, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661757

RESUMO

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

11.
PLoS Genet ; 15(1): e1007603, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30677029

RESUMO

The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.


Assuntos
Proteínas Musculares/genética , Proteínas de Neoplasias/genética , Obesidade Mórbida/genética , Receptores de Superfície Celular/genética , Magreza/genética , Fatores de Transcrição/genética , Adulto , Alelos , Índice de Massa Corporal , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/fisiopatologia , Polimorfismo de Nucleotídeo Único , Magreza/fisiopatologia
12.
Diabetes Care ; 42(7): 1202-1208, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30659074

RESUMO

OBJECTIVE: Observational studies show that higher hemoglobin A1c (A1C) predicts coronary artery disease (CAD). It remains unclear whether this association is driven entirely by glycemia. We used Mendelian randomization (MR) to test whether A1C is causally associated with CAD through glycemic and/or nonglycemic factors. RESEARCH DESIGN AND METHODS: To examine the association of A1C with CAD, we selected 50 A1C-associated variants (log10 Bayes factor ≥6) from an A1C genome-wide association study (GWAS; n = 159,940) and performed an inverse-variance weighted average of variant-specific causal estimates from CAD GWAS data (CARDIoGRAMplusC4D; 60,801 CAD case subjects/123,504 control subjects). We then replicated results in UK Biobank (18,915 CAD case subjects/455,971 control subjects) and meta-analyzed all results. Next, we conducted analyses using two subsets of variants, 16 variants associated with glycemic measures (fasting or 2-h glucose) and 20 variants associated with erythrocyte indices (e.g., hemoglobin [Hb]) but not glycemic measures. In additional MR analyses, we tested the association of Hb with A1C and CAD. RESULTS: Genetically increased A1C was associated with higher CAD risk (odds ratio [OR] 1.61 [95% CI 1.40, 1.84] per %-unit, P = 6.9 × 10-12). Higher A1C was associated with increased CAD risk when using only glycemic variants (OR 2.23 [1.73, 2.89], P = 1.0 × 10-9) and when using only erythrocytic variants (OR 1.30 [1.08, 1.57], P = 0.006). Genetically decreased Hb, with concomitantly decreased mean corpuscular volume, was associated with higher A1C (0.30 [0.27, 0.33] %-unit, P = 2.9 × 10-6) per g/dL and higher CAD risk (OR 1.19 [1.04, 1.37], P = 0.02). CONCLUSIONS: Genetic evidence supports a causal link between higher A1C and higher CAD risk. This relationship is driven not only by glycemic but also by erythrocytic, glycemia-independent factors.

14.
Am J Hum Genet ; 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30503519

RESUMO

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

15.
Nat Commun ; 9(1): 5460, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568165

RESUMO

The original version of this Article contained an error in Fig. 2. In panel a, the two legend items "rare" and "common" were inadvertently swapped. This has been corrected in both the PDF and HTML versions of the Article.

16.
Nat Commun ; 9(1): 4674, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405126

RESUMO

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens that are independent of established common variant signals (ADIPOQ and adiponectin, P = 4.2 × 10-8; APOC3 and triglyceride levels, P = 1.5 × 10-26), and identify replicating evidence for a burden associated with triglyceride levels in FAM189B (P = 2.2 × 10-8), indicating a role for this gene in lipid metabolism.

17.
Nat Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478441

RESUMO

Different exposures, including diet, physical activity, or external conditions can contribute to genotype-environment interactions (G×E). Although high-dimensional environmental data are increasingly available and multiple exposures have been implicated with G×E at the same loci, multi-environment tests for G×E are not established. Here, we propose the structured linear mixed model (StructLMM), a computationally efficient method to identify and characterize loci that interact with one or more environments. After validating our model using simulations, we applied StructLMM to body mass index in the UK Biobank, where our model yields previously known and novel G×E signals. Finally, in an application to a large blood eQTL dataset, we demonstrate that StructLMM can be used to study interactions with hundreds of environmental variables.

18.
PLoS Genet ; 14(10): e1007591, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30325923

RESUMO

A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis.

20.
J Infect Dis ; 218(11): 1700-1710, 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30010810

RESUMO

Background: Kaposi sarcoma-associated herpesvirus (KSHV) establishes lifelong infection in the human host and has been associated with a variety of malignancies. KSHV displays striking geographic variation in prevalence, which is highest in sub-Saharan Africa. The current KSHV genome sequences available are all tumor cell line-derived or primary tumor-associated viruses, which have provided valuable insights into KSHV genetic diversity. Methods: Here, we sequenced 45 KSHV genomes from a Ugandan population cohort in which KSHV is endemic; these are the only genome sequences obtained from nondiseased individuals and of KSHV DNA isolated from saliva. Results: Population structure analysis, along with the 25 published genome sequences from other parts of the world, showed whole-genome variation, separating sequences and variation within the central genome contributing to clustering of genomes by geography. We reveal new evidence for the presence of intragenic recombination and multiple recombination events contributing to the divergence of genomes into at least 5 distinct types. Discussion: This study shows that large-scale genome-wide sequencing from clinical and epidemiological samples is necessary to capture the full extent of genetic diversity of KSHV, including recombination, and provides evidence to suggest a revision of KSHV genotype nomenclature.

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