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Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS).
Gao C, Tabb KL, Dimitrov LM, Taylor KD, Wang N, Guo X, Long J, Rotter JI, Watanabe RM, Curran JE, Blangero J, Langefeld CD, Bowden DW, Palmer ND
(2018) Sci Rep 8: 5603
MeSH Terms: Adult, Apolipoprotein A-V, Atherosclerosis, Carrier Proteins, Female, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Resistance, Lipids, Lipoproteins, HDL, Mexican Americans, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, Whole Exome Sequencing
Show Abstract · Added April 10, 2018
Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h = 0.50), high-density lipoprotein (HDL, h = 0.57), total cholesterol (TC, h = 0.53), and triglyceride (TG, h = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, P = 3.67 × 10, LOD = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r = 1.0) rs189547099 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) and chr4:157997598 (P = 6.31 × 10, LOD = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 × 10). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LOD = 4.30, P = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 × 10, MAF ≥ 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, P = 4.44 × 10, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels.
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17 MeSH Terms
Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.
Jun G, Manning A, Almeida M, Zawistowski M, Wood AR, Teslovich TM, Fuchsberger C, Feng S, Cingolani P, Gaulton KJ, Dyer T, Blackwell TW, Chen H, Chines PS, Choi S, Churchhouse C, Fontanillas P, King R, Lee S, Lincoln SE, Trubetskoy V, DePristo M, Fingerlin T, Grossman R, Grundstad J, Heath A, Kim J, Kim YJ, Laramie J, Lee J, Li H, Liu X, Livne O, Locke AE, Maller J, Mazur A, Morris AP, Pollin TI, Ragona D, Reich D, Rivas MA, Scott LJ, Sim X, Tearle RG, Teo YY, Williams AL, Zöllner S, Curran JE, Peralta J, Akolkar B, Bell GI, Burtt NP, Cox NJ, Florez JC, Hanis CL, McKeon C, Mohlke KL, Seielstad M, Wilson JG, Atzmon G, Below JE, Dupuis J, Nicolae DL, Lehman D, Park T, Won S, Sladek R, Altshuler D, McCarthy MI, Duggirala R, Boehnke M, Frayling TM, Abecasis GR, Blangero J
(2018) Proc Natl Acad Sci U S A 115: 379-384
MeSH Terms: Diabetes Mellitus, Type 2, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Mexican Americans, Pedigree, Phenotype, Quantitative Trait Loci, Whole Genome Sequencing
Show Abstract · Added March 15, 2018
A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant -expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.
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15 MeSH Terms
Genome-Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex-Specific Adiposity Loci in Mexican Americans.
Gao C, Langefeld CD, Ziegler JT, Taylor KD, Norris JM, Chen YI, Hellwege JN, Guo X, Allison MA, Speliotes EK, Rotter JI, Bowden DW, Wagenknecht LE, Palmer ND
(2018) Obesity (Silver Spring) 26: 202-212
MeSH Terms: Adipose Tissue, Adiposity, Body Mass Index, Female, Genome-Wide Association Study, Genotype, Humans, Male, Mexican Americans, Middle Aged, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added March 3, 2020
OBJECTIVE - This study aimed to explore the genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity.
METHODS - A genome-wide association study of 7,757,139 single-nucleotide polymorphisms (SNPs) in 983 Mexican Americans (n  = 403; n  = 580) from the Insulin Resistance Atherosclerosis Family Study was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue, visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography.
RESULTS - The strongest signal identified was SNP rs2185405 (minor allele frequencies [MAF] = 40%; P = 1.98 × 10 ) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF = 19%) was associated with VAT in males (P = 2.39×10 ; P = 2.5 × 10 ). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6 cm increased VAT compared with noncarriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF = 14%; P = 3.07 × 10 ) in PAPPA2 and rs10923724 (MAF = 38%; P = 2.89 × 10 ) upstream of TBX15 were strongly associated with the interaction effect for VSR.
CONCLUSIONS - Six loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.
© 2017 The Obesity Society.
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KIDNEY DISEASE GENETICS AND THE IMPORTANCE OF DIVERSITY IN PRECISION MEDICINE.
Cooke Bailey JN, Wilson S, Brown-Gentry K, Goodloe R, Crawford DC
(2016) Pac Symp Biocomput 21: 285-96
MeSH Terms: Adult, African Americans, Computational Biology, Cross-Sectional Studies, European Continental Ancestry Group, Female, Gene Frequency, Genetic Variation, Health Status Disparities, Humans, Kidney Diseases, Male, Mexican Americans, Middle Aged, Nutrition Surveys, Polymorphism, Single Nucleotide, Precision Medicine, Quantitative Trait Loci, United States
Show Abstract · Added May 5, 2017
Kidney disease is a well-known health disparity in the United States where African Americans are affected at higher rates compared with other groups such as European Americans and Mexican Americans. Common genetic variants in the myosin, heavy chain 9, non-muscle (MYH9) gene were initially identified as associated with non-diabetic end-stage renal disease in African Americans, and it is now understood that these variants are in strong linkage disequilibrium with likely causal variants in neighboring APOL1. Subsequent genome-wide and candidate gene studies have suggested that MYH9 common variants among others are also associated with chronic kidney disease and quantitative measures of kidney function in various populations. In a precision medicine setting, it is important to consider genetic effects or genetic associations that differ across racial/ethnic groups in delivering data relevant to disease risk or individual-level patient assessment. Kidney disease and quantitative trait-associated genetic variants have yet to be systematically characterized in multiple racial/ethnic groups. Therefore, to further characterize the prevalence of these genetic variants and their association with kidney related traits, we have genotyped 10 kidney disease or quantitative trait-associated single nucleotide polymorphisms (SNPs) (rs2900976, rs10505955, rs10502868, rs1243400, rs9305354, rs12917707, rs17319721, rs2467853, rs2032487, and rs4821480) in 14,998 participants from the population-based cross-sectional National Health and Nutrition Examination Surveys (NHANES) III and 1999-2002 as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study. In this general adult population ascertained regardless of health status (6,293 non-Hispanic whites, 3,013 non-Hispanic blacks, and 3,542 Mexican Americans), we observed higher rates of chronic kidney disease among non-Hispanic blacks compared with the other groups as expected. We performed single SNP tests of association using linear regressions assuming an additive genetic model adjusted for age, sex, diastolic blood pressure, systolic blood pressure, and type 2 diabetes status for several outcomes including creatinine (urinary), creatinine (serum), albumin (urinary), eGFR, and albumin-to-urinary creatinine ratio (ACR). We also tested for associations between each SNP and chronic kidney disease and albuminuria using logistic regression. Surprisingly, none of the MYH9 variants tested was associated with kidney diseases or traits in non-Hispanic blacks (p>0.05), perhaps attributable to the clinical heterogeneity of kidney disease in this population. Several associations were observed in each racial/ethnic group at p<0.05, but none were consistently associated in the same direction in all three groups. The lack of significant and consistent associations is most likely due to power highlighting the importance of the availability of large, diverse populations for genetic association studies of complex diseases and traits to inform precision medicine efforts in diverse patient populations.
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19 MeSH Terms
Cross-tissue and tissue-specific eQTLs: partitioning the heritability of a complex trait.
Torres JM, Gamazon ER, Parra EJ, Below JE, Valladares-Salgado A, Wacher N, Cruz M, Hanis CL, Cox NJ
(2014) Am J Hum Genet 95: 521-34
MeSH Terms: Adipose Tissue, Analysis of Variance, Body Mass Index, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Humans, Linear Models, Mexican Americans, Mexico, Muscle, Skeletal, Phenotype, Polymorphism, Single Nucleotide, Principal Component Analysis, Quantitative Trait Loci, Texas
Show Abstract · Added February 22, 2016
Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a disproportionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (∼10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index ≥ 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues.
Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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The chromosome 3q25 genomic region is associated with measures of adiposity in newborns in a multi-ethnic genome-wide association study.
Urbanek M, Hayes MG, Armstrong LL, Morrison J, Lowe LP, Badon SE, Scheftner D, Pluzhnikov A, Levine D, Laurie CC, McHugh C, Ackerman CM, Mirel DB, Doheny KF, Guo C, Scholtens DM, Dyer AR, Metzger BE, Reddy TE, Cox NJ, Lowe WL, HAPO Study Cooperative Research Group
(2013) Hum Mol Genet 22: 3583-96
MeSH Terms: Adiposity, African Continental Ancestry Group, Asian Continental Ancestry Group, Birth Weight, Body Mass Index, Caribbean Region, Chromosomes, Human, Pair 3, Cohort Studies, Continental Population Groups, Cyclins, Ethnic Groups, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Infant, Newborn, Linear Models, Male, Mexican Americans, Pregnancy, Proteinase Inhibitory Proteins, Secretory, Serine Peptidase Inhibitor Kazal-Type 5, Thailand
Show Abstract · Added February 22, 2016
Newborns characterized as large and small for gestational age are at risk for increased mortality and morbidity during the first year of life as well as for obesity and dysglycemia as children and adults. The intrauterine environment and fetal genes contribute to the fetal size at birth. To define the genetic architecture underlying the newborn size, we performed a genome-wide association study (GWAS) in 4281 newborns in four ethnic groups from the Hyperglycemia and Adverse Pregnancy Outcome Study. We tested for association with newborn anthropometric traits (birth length, head circumference, birth weight, percent fat mass and sum of skinfolds) and newborn metabolic traits (cord glucose and C-peptide) under three models. Model 1 adjusted for field center, ancestry, neonatal gender, gestational age at delivery, parity, maternal age at oral glucose tolerance test (OGTT); Model 2 adjusted for Model 1 covariates, maternal body mass index (BMI) at OGTT, maternal height at OGTT, maternal mean arterial pressure at OGTT, maternal smoking and drinking; Model 3 adjusted for Model 2 covariates, maternal glucose and C-peptide at OGTT. Strong evidence for association was observed with measures of newborn adiposity (sum of skinfolds model 3 Z-score 7.356, P = 1.90×10⁻¹³, and to a lesser degree fat mass and birth weight) and a region on Chr3q25.31 mapping between CCNL and LEKR1. These findings were replicated in an independent cohort of 2296 newborns. This region has previously been shown to be associated with birth weight in Europeans. The current study suggests that association of this locus with birth weight is secondary to an effect on fat as opposed to lean body mass.
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23 MeSH Terms
Serum vitamins A and E as modifiers of lipid trait genetics in the National Health and Nutrition Examination Surveys as part of the Population Architecture using Genomics and Epidemiology (PAGE) study.
Dumitrescu L, Goodloe R, Brown-Gentry K, Mayo P, Allen M, Jin H, Gillani NB, Schnetz-Boutaud N, Dilks HH, Crawford DC
(2012) Hum Genet 131: 1699-708
MeSH Terms: Adult, African Americans, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, European Continental Ancestry Group, Female, Fluorescent Antibody Technique, Gene-Environment Interaction, Genetic Association Studies, Genetic Markers, Genome-Wide Association Study, Humans, Mexican Americans, Molecular Epidemiology, Nutrition Surveys, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Triglycerides, Vitamin A, Vitamin E
Show Abstract · Added December 10, 2013
Both environmental and genetic factors impact lipid traits. Environmental modifiers of known genotype-phenotype associations may account for some of the "missing heritability" of these traits. To identify such modifiers, we genotyped 23 lipid-associated variants identified previously through genome-wide association studies (GWAS) in 2,435 non-Hispanic white, 1,407 non-Hispanic black, and 1,734 Mexican-American samples collected for the National Health and Nutrition Examination Surveys (NHANES). Along with lipid levels, NHANES collected environmental variables, including fat-soluble macronutrient serum levels of vitamin A and E levels. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we modeled gene-environment interactions between vitamin A or vitamin E and 23 variants previously associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. We identified three SNP × vitamin A and six SNP × vitamin E interactions at a significance threshold of p < 2.2 × 10(-3). The most significant interaction was APOB rs693 × vitamin E (p = 8.9 × 10(-7)) for LDL-C levels among Mexican-Americans. The nine significant interaction models individually explained 0.35-1.61% of the variation in any one of the lipid traits. Our results suggest that vitamins A and E may modify known genotype-phenotype associations; however, these interactions account for only a fraction of the overall variability observed for HDL-C, LDL-C, and TG levels in the general population.
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22 MeSH Terms
Replication and characterisation of genetic variants in the fibrinogen gene cluster with plasma fibrinogen levels and haematological traits in the Third National Health and Nutrition Examination Survey.
Jeff JM, Brown-Gentry K, Crawford DC
(2012) Thromb Haemost 107: 458-67
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Blood Platelets, European Continental Ancestry Group, Female, Fibrinogen, Genetic Association Studies, Genetic Variation, Health Surveys, Humans, Male, Mexican Americans, Middle Aged, Multigene Family, Nutrition Surveys, Quantitative Trait, Heritable, Triglycerides, United States, Young Adult
Show Abstract · Added December 10, 2013
Previous genetic association studies of the fibrinogen gene cluster have identified associations with plasma fibrinogen levels. These studies are typically limited to plasma fibrinogen measured among European-descent populations. We sought to replicate previous well-known associations with fibrinogen variants and plasma fibrinogen. We then sought to identify and characterise novel associations with fibrinogen variants with plasma fibrinogen and several haematological traits in three racial/ethnic populations. We genotyped 25 single nucleotide polymorphisms (SNPs) in the fibrinogen gene cluster in 2,631 non-Hispanic whites, 2,108 non-Hispanic blacks, and 2,073 Mexican-Americans from the Third National Health and Nutrition Examination Survey (NHANES). We performed single SNP tests of association for plasma fibrinogen, mean platelet volume, platelet distribution width, platelet count, white blood cell count, and serum triglycerides. Five previously identified associations with plasma fibrinogen replicated in our study in non-Hispanic whites and blacks. We identified two novel associations between genetic variants and decreased plasma fibrinogen: rs2227395 (p=0.0007; non-Hispanic whites) and rs2070022 (p=0.001; Mexican-Americans). Several fibrinogen SNPs were also associated with haematological traits: rs6050 with decreased platelet distribution width in non-Hispanic whites; rs6050 and rs2066879 with decreased and increased platelet distribution width, respectively, in non-Hispanic whites;rs2227409 with increased mean platelet volume, rs2070017 with decreased platelet count, and rs6063 with increased platelet distribution width in non-Hispanic blacks; and rs4220 and rs2227395 with decreased white blood cell count, rs2227409 with increased platelet distribution width, rs2066860 and rs1800792 with increased and decreased triclyceride levels, respectively, and rs1800792 with decreased platelet counts in Mexican-Americans. We successfully replicated and identified novel associations with fibrinogen variants and plasma fibrinogen. These data confirm the importance of the fibrinogen gene cluster for plasma fibrinogen levels as well as suggest this gene cluster may have pleiotropic effects on haematological traits.
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Population differences in genetic risk for age-related macular degeneration and implications for genetic testing.
Spencer KL, Glenn K, Brown-Gentry K, Haines JL, Crawford DC
(2012) Arch Ophthalmol 130: 116-7
MeSH Terms: African Americans, Cross-Sectional Studies, European Continental Ancestry Group, Genetic Predisposition to Disease, Genetic Testing, Genetics, Population, Genotype, Humans, Macular Degeneration, Mexican Americans, Middle Aged, Polymorphism, Genetic, Proteins
Added December 10, 2013
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13 MeSH Terms
Evidence for age as a modifier of genetic associations for lipid levels.
Dumitrescu L, Brown-Gentry K, Goodloe R, Glenn K, Yang W, Kornegay N, Pui CH, Relling MV, Crawford DC
(2011) Ann Hum Genet 75: 589-97
MeSH Terms: Adult, African Continental Ancestry Group, Age Factors, Child, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Infant, Lipids, Male, Mexican Americans
Show Abstract · Added December 10, 2013
In order to identify novel genetic variants that influence plasma lipid concentrations, we performed a genome-wide association study (GWAS) comprised of 411 children under 18 years of age, ascertained at St. Jude Children's Research Hospital, all of whom were of European, African, or Mexican descent. Promising associations (p < 10(-5)) were subsequently examined in 1040 additional youths and 3508 adults from the Third National Health and Nutrition Examination Survey (NHANES III), a diverse population-based study. Three genotype-phenotype associations replicated in NHANES III youths and three associated in NHANES III adults at p < 0.05; however, no single association was significant in both youths and adults. The most significant association (p= 0.009) in NHANES III youths was between low-density lipoprotein cholesterol (LDL-C) and intronic rs2429917 among participants of African descent. Given the known age dependency of lipid levels, we also tested for gene-age interactions in NHANES III participants across all ages. We identified a significant (p= 0.024) age-dependent association between SGSM2 rs2429917 and LDL-C. This finding illustrates the utility of using children to discover novel variants associated with complex phenotypes and the importance of considering age-dependent genetic effects in association studies of lipid levels.
© 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.
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14 MeSH Terms