A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS)

<div><p>Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist-hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (n_max = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10^-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (<i>IDH1)</i> was associated with WAIST (rs34218846, MAF = 6.8%, P_DOM = 1.62x10^-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (<i>ZGRF1</i>; SNP rs1471880, MAF = 48.1%, P_DOM = 1.00x10^-8) were strongly associated with WHR. The exact biological function of <i>ZGRF1</i> and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10^-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (n_max = 4156) and the strongest signal was rs1471880 (P_DOM = 8.38x10^-6) in <i>ZGRF1</i> with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (<i>IDH1 and ZGRF1</i>) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, <i>IDH1</i> and <i>ZGRF1</i> warrant further evaluation.</p></div

Significant signals of association from genome-wide and exome chip association analyses in IRASFS.

<p>^aSNP identified from GWAS</p><p>^bSNP identified from exome chip</p><p>^cDominant Model</p><p>^dRecessive Model</p><p>^eMinor allele frequency based on the entire population</p><p>^fMinor/Major allele on the positive strand</p><p>Significant signals of association from genome-wide and exome chip association analyses in IRASFS.</p

Demographic characteristics of the study populations.

<p>^aHTN-IR has only 139 individuals with PBF measurements</p><p>^bValues are expressed as the mean ± standard deviation</p><p>^cIncludes 161 diabetics</p><p>Abbreviations: IRASFS, Insulin Resistance Atherosclerosis Family Study; IRAS, Insulin Resistance Atherosclerosis Study; TRIPOD, Troglitazone in Prevention of Diabetes Study; BetaGene, Family-based study of obesity, insulin resistance, and beta-cell dysfunction; HTN-IR, Hypertension-Insulin Resistance Family Study; MACAD, Mexican-American Coronary Artery Disease Study; NIDDM-Athero, NIDDM-Atherosclerosis Study.</p><p>Demographic characteristics of the study populations.</p

Regional plot of <i>IDH1</i> for association with waist circumference.

<p>(A). Analysis results in IRASFS for SNPs from genome-wide and exome chip datasets as well as de novo genotyping of the region; (B). Conditioned on rs34218846.–log₁₀(p-values) under the best fit model are indicated on the left-hand Y axis. Association analyses were computed with adjustments for age, gender, recruiting center, and admixtures with SNP rs34218846 as an additional covariate in panel B. The recombination rates are indicated on the right-hand Y axis based on HapMap. The color of each SNP annotates its correlation (r²) with the index SNP and was taken from the 1000 Genomes AMR population. A circle denotes intronic and intergenic SNPs, a triangle denotes a missense SNP, and a square denotes a SNP in the untranslated region (UTR).</p

Manhattan plots for genome-wide and exome chip association analysis in IRASFS Hispanic Americans.

<p>(A). Body Mass Index (BMI), (B). Waist Circumference (WAIST), (C). Waist-Hip Ratio (WHR), (D). Subcutaneous Adipose Tissue (SAT), (E). Visceral Adipose Tissue (VAT), and (F). Percent Body Fat (PBF). Results were adjusted for age, gender, recruitment center (San Antonio, TX or San Luis Valley, CO), and admixture estimates. P-values are shown under the best fit model. The blue line at –log₁₀(PVAL) = 4 represents a best P-value = 10⁻⁴ and the red line at –log₁₀(PVAL) = 5.5 represents a best P-value = 3.16x10^-6.</p

Regional plot of <i>ZGRF1</i> (<i>C4orf21</i>) for association with waist-hip ratio.

<p>(A). Analysis results in IRASFS for SNPs from genome-wide and exome chip datasets; (B). Conditioned on the most significant variant (rs1471880).–log₁₀(p-values) under the best fit model are indicated on the left-hand Y axis. Association analyses were computed with adjustment for age, gender, recruitment center, and admixture estimates with SNP rs1471880 as an additional covariate in panel B. The recombination rates are indicated on the right-hand Y axis based on HapMap. The color of each SNP annotates its correlation (r²) with the index SNP and was taken from the 1000 Genomes AMR population. A circle denotes intronic and intergenic SNPs, a triangle denotes a missense SNP, and a square denotes a SNP in the untranslated region (UTR).</p

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis

<div><p>Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-values_binomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.</p></div

Descriptive statistics for the age at menarche (AAM, n = 44,367) and natural menopause (ANM, n = 17,100) analytic samples.

<p>Descriptive statistics for the age at menarche (AAM, n = 44,367) and natural menopause (ANM, n = 17,100) analytic samples.</p

Generalization of five previously described age at menarche and natural menopause loci to multiple race/ethnic groups or trans-ethnically.

<p>Generalization of five previously described age at menarche and natural menopause loci to multiple race/ethnic groups or trans-ethnically.</p

Regional plots of the novel array-wide significant age at menarche (Panel A: <i>CUX2</i>) and natural menopause loci (Panels B,C: <i>FRMD5</i>, <i>GPRC5B</i>) using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women, and showing independence from previously published cardiometabolic SNP associations (shown in gray if missing).

<p>Regional plots of the novel array-wide significant age at menarche (Panel A: <i>CUX2</i>) and natural menopause loci (Panels B,C: <i>FRMD5</i>, <i>GPRC5B</i>) using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women, and showing independence from previously published cardiometabolic SNP associations (shown in gray if missing).</p