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1.
Artigo em Inglês | MEDLINE | ID: mdl-31661308

RESUMO

OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised plasma BMP9 and BMP10 levels in patients with idiopathic PAH. METHODS: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. CONCLUSIONS: Our findings demonstrate that GDF2 mutations result in BMP9 loss-of-function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH.

3.
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.

4.
Nat Genet ; 51(7): 1137-1148, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31253982

RESUMO

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.

5.
Trends Mol Med ; 25(8): 662-672, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31221572

RESUMO

Despite the identification of several dozens of common genetic variants associated with Alzheimer's disease (AD) and Parkinson's disease (PD), most of the genetic risk remains uncharacterised. Therefore, it is important to understand the role of regulatory elements, such as miRNAs. Dysregulated miRNAs are implicated in AD and PD, with potential value in dissecting the shared pathophysiology between the two disorders. miRNAs relevant to both neurodegenerative diseases are related to axonal guidance, apoptosis, and inflammation, therefore, AD and PD likely arise from similar underlying biological pathway defects. Furthermore, pathways regulated by APP, L1CAM, and genes of the caspase family may represent promising therapeutic miRNA targets in AD and PD since they are targeted by dysregulated miRNAs in both disorders.

6.
Gene ; 707: 1-8, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31054364

RESUMO

BACKGROUND: Genome-wide association studies have captured a large proportion of genetic variation related to type 1 diabetes mellitus (T1D). However, most of these studies are performed in populations of European ancestry and therefore the disease risk estimations can be inaccurate when extrapolated to other world populations. METHODS: We conducted a case-control study in 1866 individuals from the three major populations of the Republic of Bashkortostan (Russians, Tatars, and Bashkirs) in Russian Federation, using single-locus and multilocus approach to identify genetic predictors of T1D. RESULTS: We found that LTA rs909253 and TNF rs1800629 polymorphisms were associated with T1D in the group of Tatars. Meta-analysis of the association study results in the three ethnic groups has confirmed the association between the T1D risk and LTA rs909253 genetic variant. LTA rs909253 and TNF rs1800629 loci were also featured in combinations most significantly associated with T1D. CONCLUSION: Our findings suggest that LTA rs909253 and TNF rs1800629 polymorphisms are associated with the risk of T1D both independently and in combination with polymorphic markers in other inflammatory genes, and the analysis of multi-allelic combinations provides valuable insight in the study of polygenic traits.


Assuntos
Diabetes Mellitus Tipo 1/genética , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Bashkiria/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Int J Epidemiol ; 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31074781

RESUMO

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) is positively associated with offspring birth weight (BW) and BMI in childhood and adulthood. Each of these associations could be due to causal intrauterine effects, or confounding (genetic or environmental), or some combination of these. Here we estimate the extent to which the association between maternal BMI and offspring body size is explained by offspring genotype, as a first step towards establishing the importance of genetic confounding. METHODS: We examined the associations of maternal pre-pregnancy BMI with offspring BW and BMI at 1, 5, 10 and 15 years, in three European birth cohorts (n ≤11 498). Bivariate Genomic-relatedness-based Restricted Maximum Likelihood implemented in the GCTA software (GCTA-GREML) was used to estimate the extent to which phenotypic covariance was explained by offspring genotype as captured by common imputed single nucleotide polymorphisms (SNPs). We merged individual participant data from all cohorts, enabling calculation of pooled estimates. RESULTS: Phenotypic covariance (equivalent here to Pearson's correlation coefficient) between maternal BMI and offspring phenotype was 0.15 [95% confidence interval (CI): 0.13, 0.17] for offspring BW, increasing to 0.29 (95% CI: 0.26, 0.31) for offspring 15 year BMI. Covariance explained by offspring genotype was negligible for BW [-0.04 (95% CI: -0.09, 0.01)], but increased to 0.12 (95% CI: 0.04, 0.21) at 15 years, which is equivalent to 43% (95% CI: 15%, 72%) of the phenotypic covariance. Sensitivity analyses using weight, BMI and ponderal index as the offspring phenotype at all ages showed similar results. CONCLUSIONS: Offspring genotype explains a substantial fraction of the covariance between maternal BMI and offspring adolescent BMI. This is consistent with a potentially important role for genetic confounding as a driver of the maternal BMI-offspring BMI association.

8.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 428-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30593698

RESUMO

Anorexia nervosa (AN) occurs nine times more often in females than in males. Although environmental factors likely play a role, the reasons for this imbalanced sex ratio remain unresolved. AN displays high genetic correlations with anthropometric and metabolic traits. Given sex differences in body composition, we investigated the possible metabolic underpinnings of female propensity for AN. We conducted sex-specific GWAS in a healthy and medication-free subsample of the UK Biobank (n = 155,961), identifying 77 genome-wide significant loci associated with body fat percentage (BF%) and 174 with fat-free mass (FFM). Partitioned heritability analysis showed an enrichment for central nervous tissue-associated genes for BF%, which was more prominent in females than males. Genetic correlations of BF% and FFM with the largest GWAS of AN by the Psychiatric Genomics Consortium were estimated to explore shared genomics. The genetic correlations of BF%male and BF%female with AN differed significantly from each other (p < .0001, δ = -0.17), suggesting that the female preponderance in AN may, in part, be explained by sex-specific anthropometric and metabolic genetic factors increasing liability to AN.

9.
Biomark Med ; 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30191727

RESUMO

AIM: The aim of the study was to explore the effects of variants at 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and kinesin family member 6 (KIF6) loci on a range of cardio-metabolic phenotypes. METHODS: We analyzed the range of variants within Genetics in Brisighella Health Study and KIF6 genes using an additive genetic model on 18 cardiometabolic phenotypes in a sample of 1645 individuals from the Genetics in Brisighella Health Study and replicated in 10,662 individuals from the Estonian Genome Center University of Tartu. RESULTS: We defined directly the effects of rs3846662:C>A at HMGCR on apoB levels. The analysis also confirmed effects of on low-density lipoprotein-cholesterol and total cholesterol levels. Variants in KIF6 gene did not reveal any associations with cardiometabolic phenotypes. CONCLUSION: This study highlights effect of HMGCR locus on assay-determined apoB levels, an infrequent measure of blood lipids in large studies.

10.
Int J Obes (Lond) ; 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120425

RESUMO

BACKGROUND: The prevention of the risk of type 2 diabetes (T2D) is complicated by multidimensional interplays between biological and psychosocial factors acting at the individual level. To address the challenge we took a systematic approach, to explore the bio-psychosocial predictors of blood glucose in mid-age. METHODS: Based on the 31-year and 46-year follow-ups (5,078 participants, 43% male) of Northern Finland Birth Cohort 1966, we used a systematic strategy to select bio-psychosocial variables at 31 years to enable a data-driven approach. As selection criteria, the variable must be (i) a component of the metabolic syndrome or an indicator of psychosocial health using WHO guidelines, (ii) easily obtainable in general health check-ups and (iii) associated with fasting blood glucose at 46 years (P < 0.10). Exploratory and confirmatory factor analysis were used to derive latent factors, and stepwise linear regression allowed exploration of relationships between factors and fasting glucose. RESULTS: Of all 26 variables originally considered, 19 met the selection criteria and were included in an exploratory factor analysis. Two variables were further excluded due to low loading (<0.3). We derived four latent factors, which we named as socioeconomic, metabolic, psychosocial and blood pressure status. The combination of metabolic and psychosocial factors, adjusted for sex, provided best prediction of fasting glucose at 46 years (explaining 10.7% of variation in glucose; P < 0.001). Regarding different bio-psychosocial pathways and relationships, the importance of psychosocial factors in addition to established metabolic risk factors was highlighted. CONCLUSIONS: The present study supports evidence for the bio-psychosocial nature of adult glycemic health and exemplifies an evidence-based approach to model the bio-psychosocial relationships. The factorial model may help further research and public health practice in focusing also on psychosocial aspects in maintaining normoglycaemia in the prevention of cardio-metabolic diseases.

11.
Nat Commun ; 9(1): 1416, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29650961

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-ß pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.


Assuntos
Adenosina Trifosfatases/química , Aquaporina 1/química , Hipertensão Pulmonar Primária Familiar/genética , Fatores de Diferenciação de Crescimento/química , Proteínas de Membrana Transportadoras/química , Mutação , Fatores de Transcrição SOXF/química , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Adulto , Aquaporina 1/genética , Aquaporina 1/metabolismo , Sequência de Bases , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Estudos de Casos e Controles , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/metabolismo , Hipertensão Pulmonar Primária Familiar/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Fatores de Diferenciação de Crescimento/genética , Fatores de Diferenciação de Crescimento/metabolismo , Células HEK293 , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Modelos Moleculares , Prognóstico , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Sequenciamento Completo do Genoma
12.
J Clin Endocrinol Metab ; 103(3): 991-1004, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325096

RESUMO

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. Objective: To investigate the genetic regulation of serum E2 and E1 in men. Design, Setting, and Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts. Main Outcome Measures: Genetic determinants of serum E2 and E1 levels. Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance. Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.


Assuntos
Aromatase/genética , Densidade Óssea/genética , Estradiol/sangue , Densidade Óssea/fisiologia , Cromossomos Humanos X , Estudos de Coortes , Estradiol/genética , Estradiol/fisiologia , Estrona/sangue , Estrona/genética , Feminino , Regulação da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Genótipo , Hormônios Esteroides Gonadais/sangue , Humanos , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Vértebras Lombares/fisiologia , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Testosterona/sangue
13.
Hum Mol Genet ; 27(3): 546-558, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186428

RESUMO

Progranulin is a secreted protein with important functions in processes including immune and inflammatory response, metabolism and embryonic development. The present study aimed at identification of genetic factors determining progranulin concentrations. We conducted a genome-wide association meta-analysis for serum progranulin in three independent cohorts from Europe: Sorbs (N = 848) and KORA (N = 1628) from Germany and PPP-Botnia (N = 335) from Finland (total N = 2811). Single nucleotide polymorphisms (SNPs) associated with progranulin levels were replicated in two additional German cohorts: LIFE-Heart Study (Leipzig; N = 967) and Metabolic Syndrome Berlin Potsdam (Berlin cohort; N = 833). We measured mRNA expression of genes in peripheral blood mononuclear cells (PBMC) by micro-arrays and performed mRNA expression quantitative trait and expression-progranulin association studies to functionally substantiate identified loci. Finally, we conducted siRNA silencing experiments in vitro to validate potential candidate genes within the associated loci. Heritability of circulating progranulin levels was estimated at 31.8% and 26.1% in the Sorbs and LIFE-Heart cohort, respectively. SNPs at three loci reached study-wide significance (rs660240 in CELSR2-PSRC1-MYBPHL-SORT1, rs4747197 in CDH23-PSAP and rs5848 in GRN) explaining 19.4%/15.0% of the variance and 61%/57% of total heritability in the Sorbs/LIFE-Heart Study. The strongest evidence for association was at rs660240 (P = 5.75 × 10-50), which was also associated with mRNA expression of PSRC1 in PBMC (P = 1.51 × 10-21). Psrc1 knockdown in murine preadipocytes led to a consecutive 30% reduction in progranulin secretion. In conclusion, the present meta-GWAS combined with mRNA expression identified three loci associated with progranulin and supports the role of PSRC1 in the regulation of progranulin secretion.

14.
Eur J Hum Genet ; 25(11): 1179-1180, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29023438
15.
Eur J Hum Genet ; 25(8): 988-994, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28537275

RESUMO

Genome-wide association studies have facilitated the discovery of thousands of loci for hundreds of phenotypes. However, the issue of missing heritability remains unsolved for most complex traits. Locus discovery could be enhanced with both improved power through multi-phenotype analysis (MPA) and use of a wider allele frequency range, including rare variants (RVs). MPA methods for single-variant association have been proposed, but given their low power for RVs, more efficient approaches are required. We propose multi-phenotype analysis of rare variants (MARV), a burden test-based method for RVs extended to the joint analysis of multiple phenotypes through a powerful reverse regression technique. Specifically, MARV models the proportion of RVs at which minor alleles are carried by individuals within a genomic region as a linear combination of multiple phenotypes, which can be both binary and continuous, and the method accommodates directly the genotyped and imputed data. The full model, including all phenotypes, is tested for association for discovery, and a more thorough dissection of the phenotype combinations for any set of RVs is also enabled. We show, via simulations, that the type I error rate is well controlled under various correlations between two continuous phenotypes, and that the method outperforms a univariate burden test in all considered scenarios. Application of MARV to 4876 individuals from the Northern Finland Birth Cohort 1966 for triglycerides, high- and low-density lipoprotein cholesterols highlights known loci with stronger signals of association than those observed in univariate RV analyses and suggests novel RV effects for these lipid traits.


Assuntos
Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Modelos Genéticos , Algoritmos , Colesterol/sangue , Colesterol/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino
16.
BMC Bioinformatics ; 18(1): 110, 2017 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-28209135

RESUMO

BACKGROUND: Genome-wide association studies have enabled identification of thousands of loci for hundreds of traits. Yet, for most human traits a substantial part of the estimated heritability is unexplained. This and recent advances in technology to produce high-dimensional data cost-effectively have led to method development beyond standard common variant analysis, including single-phenotype rare variant and multi-phenotype common variant analysis, with the latter increasing power for locus discovery and providing suggestions of pleiotropic effects. However, there are currently no optimal methods and tools for the combined analysis of rare variants and multiple phenotypes. RESULTS: We propose a user-friendly software tool MARV for Multi-phenotype Analysis of Rare Variants. The tool is based on a method that collapses rare variants within a genomic region and models the proportion of minor alleles in the rare variants on a linear combination of multiple phenotypes. MARV provides analyses of all phenotype combinations within one run and calculates the Bayesian Information Criterion to facilitate model selection. The running time increases with the size of the genetic data while the number of phenotypes to analyse has little effect both on running time and required memory. We illustrate the use of MARV with analysis of triglycerides (TG), fasting insulin (FI) and waist-to-hip ratio (WHR) in 4,721 individuals from the Northern Finland Birth Cohort 1966. The analysis suggests novel multi-phenotype effects for these metabolic traits at APOA5 and ZNF259, and at ZNF259 provides stronger support for association (P TG+FI = 1.8 × 10-9) than observed in single phenotype rare variant analyses (P TG = 6.5 × 10-8 and P FI = 0.27). CONCLUSIONS: MARV is a computationally efficient, flexible and user-friendly software tool allowing rapid identification of rare variant effects on multiple phenotypes, thus paving the way for novel discoveries and insights into biology of complex traits.


Assuntos
Biologia Computacional/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Software , Genótipo , Humanos
17.
BMC Bioinformatics ; 18(1): 25, 2017 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-28077070

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) of single nucleotide polymorphisms (SNPs) have been successful in identifying loci contributing genetic effects to a wide range of complex human diseases and quantitative traits. The traditional approach to GWAS analysis is to consider each phenotype separately, despite the fact that many diseases and quantitative traits are correlated with each other, and often measured in the same sample of individuals. Multivariate analyses of correlated phenotypes have been demonstrated, by simulation, to increase power to detect association with SNPs, and thus may enable improved detection of novel loci contributing to diseases and quantitative traits. RESULTS: We have developed the SCOPA software to enable GWAS analysis of multiple correlated phenotypes. The software implements "reverse regression" methodology, which treats the genotype of an individual at a SNP as the outcome and the phenotypes as predictors in a general linear model. SCOPA can be applied to quantitative traits and categorical phenotypes, and can accommodate imputed genotypes under a dosage model. The accompanying META-SCOPA software enables meta-analysis of association summary statistics from SCOPA across GWAS. Application of SCOPA to two GWAS of high-and low-density lipoprotein cholesterol, triglycerides and body mass index, and subsequent meta-analysis with META-SCOPA, highlighted stronger association signals than univariate phenotype analysis at established lipid and obesity loci. The META-SCOPA meta-analysis also revealed a novel signal of association at genome-wide significance for triglycerides mapping to GPC5 (lead SNP rs71427535, p = 1.1x10-8), which has not been reported in previous large-scale GWAS of lipid traits. CONCLUSIONS: The SCOPA and META-SCOPA software enable discovery and dissection of multiple phenotype association signals through implementation of a powerful reverse regression approach.


Assuntos
Índice de Massa Corporal , HDL-Colesterol/genética , LDL-Colesterol/genética , Estudo de Associação Genômica Ampla/métodos , Obesidade/genética , Triglicerídeos/genética , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Humanos , Modelos Teóricos , Obesidade/metabolismo , Fenótipo , Software , Triglicerídeos/metabolismo
18.
Nat Commun ; 7: 13357, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27876822

RESUMO

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.


Assuntos
Antropometria , Tamanho Corporal , Modelos Genéticos , Análise de Componente Principal , Estudo de Associação Genômica Ampla , Genótipo , Humanos
19.
Diabetes ; 65(10): 3200-11, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27416945

RESUMO

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.


Assuntos
Quimiocinas CC/genética , Estudo de Associação Genômica Ampla/métodos , Resistência à Insulina/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Quimiocinas CC/fisiologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/fisiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia
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