Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population

Comuzzie, Anthony G.; Cole, Shelley A.; Laston, Sandra; Voruganti, V. Saroja; Haack, Karin; Gibbs, Richard A.; Butte, Nancy F.

doi:10.1371/journal.pone.0051954

Cited by 356 publications

(328 citation statements)

References 57 publications

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“…The KLHL29 locus is highly complex and seems to encode multiple proteins containing BTB and kelch motifs but with poorly annotated functions. NAT2 was significant for the joint CVD+T2D end point in our study and was previously detected as a GWAS signal for several important cardiometabolic traits including total cholesterol, triglyceride, 31 and insulin sensitivity (GENESIS consortium, personal communication) that are relevant for both CVD and T2D. NAT2 (N-acetyltransferase 2) is a well-known pharmacogenetic gene responsible for O-and N-acetylation of arylamine and hydrazine drugs and carcinogens but the mechanisms linking NAT2 to cardiometabolic traits are unknown.…”

Section: Discussionsupporting

confidence: 65%

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Chan

Huang

Meng

et al. 2014

Circ Cardiovasc Genet

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It has long been known that cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors and pathophysiological intermediaries including obesity, dyslipidemia, insulin resistance, and proinflammatory and prothrombotic states. [1][2][3] However, the key molecular drivers underlying these highly correlated phenotypes as well as the potential regulatory networks shared in the pathogenesis of CVD and T2D remain poorly understood. Clinical Perspective on p 919Of the ≈60 genetic loci identified for CVD and T2D in large-scale genome-wide association studies (GWAS), 5 only 2 significant loci (TCF7L2 and VEGFA) are shared between the 2 diseases. There are ≥3 fundamentally important questions that remain to be answered. First, are there additional genetic risks, either alone or concentrated in specific regulatory networks that may explain the pathophysiological connections between CVD and T2D? Second, are there any ethnicityspecific genetic mechanisms for these 2 common vascular diseases, given that there are drastic ethnicity-specific differences in their risk and linkage disequilibrium patterns. [6][7][8] Third, although common genetic loci have been detected across different populations (eg, the Chr9p21 locus for CVD and the TCF7L2 locus for T2D) supporting the presence of common pathological paths across ethnicity, to what degree molecular mechanisms are shared across ethnicities?To answer these 3 questions, we performed 2 GWAS for both CVD and T2D using an integrative pathway and network analysis in the national Women's Health Initiative SNP Health Association Resource (WHI-SHARe) and the Genomics and Background-Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results-Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions-Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory ge...

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Section: Discussionsupporting

confidence: 65%

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Chan

Huang

Meng

et al. 2014

Circ Cardiovasc Genet

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“…The nine GWAS SNPs that have giSNPs in the 1,000 genomes dataset were reported in a total of four separate GWAS (Do et al, 2011;Comuzzie et al, 2012;Demirkan et al, 2012;Seppala et al, 2014). In most cases, the SNP did not have a highly significant p-value, and was often reported as suggestive.…”

Section: Genetically Indistinguishable Snps In Humansmentioning

confidence: 99%

Sporadic, Global Linkage Disequilibrium Between Unlinked Segregating Sites

2015

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Demographic, genetic, or stochastic factors can lead to perfect linkage disequilibrium (LD) between alleles at two loci without respect to the extent of their physical distance, a phenomenon that Lawrence et al. (2005a) refer to as "genetic indistinguishability." This phenomenon can complicate genotype-phenotype association testing by hindering the ability to localize causal alleles, but has not been thoroughly explored from a theoretical perspective or using large, dense whole-genome polymorphism data sets. We derive a simple theoretical model of the prevalence of genetic indistinguishability between unlinked loci and verify its accuracy via simulation. We show that sample size and minor allele frequency are the major determinants of the prevalence of perfect LD between unlinked loci but that demographic factors, such as deviations from random mating, can produce significant effects as well. Finally, we quantify this phenomenon in three model organisms and find thousands of pairs of moderate-frequency ( . 5%) genetically indistinguishable variants in relatively large data sets. These results clarify a previously underexplored population genetic phenomenon with important implications for association studies and define conditions under which it is likely to manifest.KEYWORDS linkage disequilibrium; genome-wide association study; genetically indistinguishable A basic genomic property of sexually reproducing organisms is genetic disequilibrium, the nonrandom association between alleles at two or more loci. This quantity is often referred to as linkage disequilibrium (LD) to emphasize the important role of genetic linkage in generating and maintaining the association at physically proximal loci. The concept of LD as a property of two loci that are physically near each other is a natural viewpoint given the large body of theoretical and empirical work characterizing mechanisms by which demography and selection influence patterns of LD between physically proximal loci. The existence and extent of LD between linked loci is influenced by the demographic history of a population, reveals locus-specific selective forces, and is a critical parameter governing the resolution of marker-trait association studies (reviewed in Slatkin 2008). Nevertheless, it is well known that physically distant or even independently segregating loci can also exhibit nonrandom associations.Specifically, LD between alleles segregating at physically unlinked loci can be induced by a variety of forces such as selection, genetic drift, nonrandom mating, epistasis, pleiotropy, and nonrandom chromosome transmission (Michie 1953;Bennett and Binet 1956;Nei 1967;Crow and Kimura 1970;Lewontin 1988;Petkov et al. 2005;Platt et al. 2010;Rohlfs et al. 2010;Corbett-Detig et al. 2013;Long et al. 2013). In this article we examine nonrandom associations between alleles at pairs of physically unlinked loci. We use the term LD to describe these associations but stress that they are not a result of genetic linkage between the loci.For two main reasons, a co...

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“…FAM110A synthesizes a protein that participates in the cell cycle progression, whose role is related to the formation of the centrosome/spindle pole fibers during mitosis (Hauge et al, 2007). In a GWAS in humans, this gene was associated with body measures (waist height) (Comuzzie et al, 2012). SNPs in the gene are associated with growth traits in both species.…”

Section: Chromosomementioning

confidence: 99%

Associations between single nucleotide polymorphisms and carcass traits in Nellore cattle using high-density panels

Espigolan¹,

Baldi²,

Boligon³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The objective of this study was to evaluate associations between single nucleotide polymorphism (SNP) markers and carcass traits measured postmortem in Nellore cattle. Records of loin eye area (LEA) and backfat thickness (BF) from 740 males and records of hot carcass weight (HCW) from 726 males were analyzed. All of the animals were genotyped using the BovineHD BeadChip. Association analyses were performed by the restricted maximum likelihood method that considered one SNP at a time. Significant SNPs were identified on (2015) chromosomes 2 and 6 for LEA and on chromosomes 7, 1, and 2 for BF. For HCW, associations with SNPs were found on chromosomes 13, 14, and 28, in addition to genome regions that were directly related to this trait, such as the EFCAB8 and VSTM2L genes, and to bone development (RHOU). Some SNPs were located in very close proximity to genes involved in basal metabolism (BLCAP, NNAT, CTNNBL1, TGM2, and LOC100296770) and the immune system (BPI).

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Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population

Cited by 356 publications

References 57 publications

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Sporadic, Global Linkage Disequilibrium Between Unlinked Segregating Sites

Associations between single nucleotide polymorphisms and carcass traits in Nellore cattle using high-density panels

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