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1.  Correction: A whole genome association study of mother-to-child transmission of HIV in Malawi 
Genome Medicine  2010;2(10):76.
A correction to: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick andthe NIAID Center for HIV/AIDS Vaccine Immunology. A whole genome association study of mother-to-child transmission of HIV in Malawi. Genome Medicine 2010, 2:17.
doi:10.1186/gm197
PMCID: PMC3092107  PMID: 21083872
2.  Associations of body mass index with incident hypertension in American white, American black and Chinese Asian adults in early and middle adulthood: the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Atherosclerosis Risk in Communities (ARIC) study and the People’s Republic of China (PRC) study 
The association of body mass index (BMI) with blood pressure may be stronger in Asian than non-Asian populations, however, longitudinal studies with direct comparisons between ethnicities are lacking. We compared the relationship of BMI with incident hypertension over approximately 9.5 years of follow-up in young (24-39 years) and middle-aged (45-64 years) Chinese Asians (n=5354), American Blacks (n=6076) and American Whites (n=13451). We estimated risk differences using logistic regression models and calculated adjusted incidences and incidence differences. To facilitate comparisons across ethnicities, standardized estimates were calculated using mean covariate values for age, sex, smoking, education and field center, and included the quadratic terms for BMI and age. Weighted least-squares regression models with were constructed to summarize ethnic-specific incidence differences across BMI. Wald statistics and p-values were calculated based on chi-square distributions. The association of BMI with the incidence difference for hypertension was steeper in Chinese (p<0.05) than in American populations during young and middle-adulthood. For example, at a BMI of 25 vs 21 kg/m2 the adjusted incidence differences per 1000 persons (95% CI) in young adults with a BMI of 25 vs those with a BMI of 21 was 83 (36-130) for Chinese, 50 (26-74) for Blacks and 30 (12-48) for Whites; among middle-aged adults it was 137 (77-198) for Chinese, 49 (9-88) for Blacks and 54 (38-69) for Whites. Whether hypertension carries the same level of risk of stroke or cardiovascular disease across national or ethnic groups remains uncertain.
PMCID: PMC4053207  PMID: 24231024
blood pressure; multi-ethnic; obesity; African American; cardiovascular disease
3.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
Background
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Methods
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
Results
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
Conclusions
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
doi:10.1016/j.atherosclerosis.2013.02.038
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
4.  The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study 
Atherosclerosis  2013;228(1):175-180.
Objectives
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to hepatic inflammation to cirrhosis. We sought to identify common genetic variants contributing to NAFLD, using CT measured fatty liver (FL), and alanine aminotransferase levels (ALT), as a biochemical marker of hepatic inflammation.
Methods
We employed a correlated meta-analysis (CMA) to test whether combining FL and ALT genomewide association (GWA) results, using ~2.5 million imputed SNPs, could enhance ability to detect variants influencing both traits.
Results
Variants of the ERLIN1-CHUK-CWF19L1 gene cluster were associated with concomitant variation of FL and ALT. Nine variants (rs2862954, rs1408579, rs10883451, rs11597086, rs11591741, rs17729876, rs17668255, rs17668357, rs12784396) displayed genomewide significant associations at loci concomitantly influencing FL and ALT (2.47×10−9≤CMA-p≤4.29×10−10) as compared with the suggestive significance of marginal tests (4.11×10−5≤GWA-p≤2.34×10−6). For example, the missense variant in ERLIN1-rs2862954 was genomewide significant (CMA-p=4.88×10−10) for the combination of FL and ALT, while the respective univariate associations were suggestive (FL:p=5.74×10−6, ALT:p=3.71×10−6). Further we investigated whether the concomitant associations were driven mainly by ALT levels. When we adjusted FL by ALT, the correlated associations diminished but did not vanish (CMA-p≤3.3×10−7). Our findings suggest ERLIN1-CHUK-CWF19L1 variants are associated with early stage of FL accumulation (measured by CT) to hepatic inflammation (ALT levels), and the association enhances when accounting for the correlations between their scans.
Conclusions
CMA approach enhanced the ability to identify novel variants of the ERLIN1-CHUK-CWF19L1 influencing both simple steatosis and hepatic steatosis with inflammation, which suggest that this gene cluster may regulate the susceptibility of NAFLD in a wide spectrum of disease.
doi:10.1016/j.atherosclerosis.2013.01.038
PMCID: PMC3640729  PMID: 23477746
5.  Sex-influenced Association of Nonalcoholic Fatty Liver Disease with Coronary Heart Disease 
Atherosclerosis  2013;227(2):420-424.
Objective
This study investigated whether nonalcoholic fatty liver disease (NAFLD) predicts prevalent coronary heart disease (CHD).
Methods
Epidemiologic studies have used various definitions for NAFLD. Here, we considered both liver fat burden measured by CT (FL) and the non-specific measure of hepatic inflammation –alanine aminotransferase (ALT). The association of FL and ALT with CHD (self report of coronary bypass, myocardial infarction, or percutaneous transluminal coronary angioplasty) was investigated in 2,756 European-American participants of the Family Heart Study.
Results
FL (p=0.0084) and ALT (≥40U/L, p=0.014) were each individually associated with prevalent CHD. However, when accounting for traditional metabolic risk factors in a multivariate model FL had no predictive value for CHD in either men or women; whereas ALT was a significant predictor of CHD in men, and the association strengthened among non-diabetic men. In non-diabetic women, neither FL nor ALT was associated with CHD.
Conclusions
ALT (≥40U/L) was a predictor of prevalent CHD in men but not in women, while CT measured FL was not significant in either sex. The failure to account for traditional risk factors, heterogeneity by sex, and varying definitions of NAFLD may account for some of the conflicting evidence in the literature regarding the association between NAFLD and coronary disease.
doi:10.1016/j.atherosclerosis.2013.01.013
PMCID: PMC3602396  PMID: 23390892
cardiovascular disease; nonalcoholic steatohepatitis; sex-specific association; insulin resistance; glucose metabolism
6.  A Candidate Gene Study of Tardive Dyskinesia in the CATIE Schizophrenia Trial 
Tardive dyskinesia (TD) is a movement disorder characterized by involuntary oro-facial, limb, and truncal movements. As a genetic basis for inter-individual variation is assumed, there have been a sizeable number of candidate gene studies. All subjects met diagnostic criteria for schizophrenia and were randomized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project (CATIE). TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals. Probable TD was defined as meeting Schooler–Kane criteria at any scheduled CATIE visit (207/710 subjects, 29.2%). A total of 128 candidate genes were studied in 710 subjects—2,580 SNPs in 118 candidate genes selected from the literature (e.g., dopamine, serotonin, glutamate, and GABA pathways) and composite genotypes for 10 drug-metabolizing enzymes. No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons. Thus, we found no support for either novel or prior associations from the literature.
doi:10.1002/ajmg.b.30981
PMCID: PMC3894657  PMID: 19475583
schizophrenia; tardive dyskinesia; antipsychotic medication; adverse drug reaction; genetic; candidate gene association
7.  Interactions Between Obesity, Parental History of Hypertension, and Age on Prevalent Hypertension: The People’s Republic of China Study 
Age, family history, and body mass index (BMI) influence the prevalence of hypertension, but very little is known about the interplay of these factors in Chinese populations. The authors examined this issue in Chinese adults (n = 4104) in the People’s Republic of China Study. In young adults (24–39 years), the prevalence of hypertension/1000 persons (95% confidence interval [CI]) at the referent BMI was greater among subjects with a parental history of hypertension (35; 15–54) compared with those without (7; 3–11). Among middle-aged (40–71 years) adults, the prevalence of hypertension was similar regardless of parental history; however, the effect of BMI was modified by parental history status. For example, at BMI = 25 kg/m2, the prevalence difference/1000 persons was 375 (95% CI = 245–506) and 97 (95% CI = 51–144) among subjects with and without a parental history, respectively. These large differences call for further investigation of the genetic and environmental factors that could be driving this interaction.
doi:10.1177/1010539511409393
PMCID: PMC3298639  PMID: 21653607
Asian; blood pressure; body mass index; Chinese; family history
8.  Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study 
BMC Medical Genetics  2013;14:98.
Background
Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.
Methods
As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.
Results
Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.
Conclusions
Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
doi:10.1186/1471-2350-14-98
PMCID: PMC3849560  PMID: 24063630
9.  Generalization and Dilution of Association Results from European GWAS in Populations of Non-European Ancestry: The PAGE Study 
PLoS Biology  2013;11(9):e1001661.
A multi-ethnic study demonstrates that the extrapolation of genetic disease risk models from European populations to other ethnicities is compromised more strongly by genetic structure than by environmental or global genetic background in differential genetic risk associations across ethnicities.
The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.
Author Summary
The number of known associations between human diseases and common genetic variants has grown dramatically in the past decade, most being identified in large-scale genetic studies of people of Western European origin. But because the frequencies of genetic variants can differ substantially between continental populations, it's important to assess how well these associations can be extended to populations with different continental ancestry. Are the correlations between genetic variants, disease endpoints, and risk factors consistent enough for genetic risk models to be reliably applied across different ancestries? Here we describe a systematic analysis of disease outcome and risk-factor–associated variants (tagSNPs) identified in European populations, in which we test whether the effect size of a tagSNP is consistent across six populations with significant non-European ancestry. We demonstrate that although nearly all such tagSNPs have effects in the same direction across all ancestries (i.e., variants associated with higher risk in Europeans will also be associated with higher risk in other populations), roughly a quarter of the variants tested have significantly different magnitude of effect (usually lower) in at least one non-European population. We therefore advise caution in the use of tagSNP-based genetic disease risk models in populations that have a different genetic ancestry from the population in which original associations were first made. We then show that this differential strength of association can be attributed to population-dependent variations in the correlation between tagSNPs and the variant that actually determines risk—the so-called functional variant. Risk models based on functional variants are therefore likely to be more robust than tagSNP-based models.
doi:10.1371/journal.pbio.1001661
PMCID: PMC3775722  PMID: 24068893
10.  Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women’s Health Initiative SHARe Study 
Human genetics  2012;132(3):323-336.
Genome-wide association studies of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G×E) interactions in post-menopausal African-American and Hispanic women from the Women’s Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N=8,203) and 786,776 SNPs from Hispanics (N=3,484). Tests of G×E interaction at all SNPs for recreational physical activity (met-hrs/wk), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G×E interaction terms. The strongest evidence for concordant G×E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P=0.70, beta=−0.01, P=3.81×10−7) with BMI as the outcome. The strongest evidence for G×E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP×kcal =−0.04, P=2.17×10−7). No results exceeded the Bonferroni–corrected statistical significance threshold.
doi:10.1007/s00439-012-1246-3
PMCID: PMC3704217  PMID: 23192594
BMI; WHR; genetic epidemiology; disparity; obesity; GWAS
11.  The association of diabetes with breast cancer incidence and mortality in the Long Island Breast Cancer Study Project 
Cancer causes & control : CCC  2012;23(7):1193-1203.
Purpose
Diabetes has been associated with increased risk of breast cancer in a number of epidemiologic studies, but its effects on survival among women diagnosed with breast cancer have been examined less frequently. Importantly, prior investigations have rarely considered the influence of factors associated with diabetes such as obesity, age at diabetes diagnosis, duration of diabetes, or diabetes treatments.
Methods
We evaluated the effect of self-reported diabetes on breast cancer incidence and mortality in the Long Island Breast Cancer Study Project, which includes 1,447 breast cancer cases and 1,453 controls. Follow-up data for all-cause (n = 395) and 5-year breast cancer-specific mortality (n = 104) through December 2005 were determined for case women from the National Death Index. Adjusted logistic regression and Cox proportional hazards models were used to estimate odds ratios (OR) and hazards ratios (HR), respectively.
Results
Postmenopausal women with diabetes were at increased risk of developing breast cancer [OR = 1.35; 95 % confidence interval (CI) = 0.99–1.85], as were those who were not of white race regardless of menopausal status [OR = 3.89; 95 % CI = 1.66–9.11]. Among case women, diabetes was associated with a modestly increased risk of death from all causes [HR = 1.65; 95 % CI = 1.18–2.29], an association that was stronger in women who were obese at breast cancer diagnosis [HR = 2.49; 94 % CI = 1.58–3.93]. In analyses restricted to diabetics, there was no statistically significant effect of duration of diabetes or type of treatment on breast cancer incidence or mortality.
Conclusions
Our findings suggest that diabetes may increase incidence of breast cancer in older women and non-whites, and mortality due to all causes.
doi:10.1007/s10552-012-9989-7
PMCID: PMC3383781  PMID: 22674293
Breast cancer; Diabetes; Survival
12.  The 9p21 genetic variant is additive to carotid intima media thickness and plaque in improving coronary heart disease risk prediction in white participants of the Atherosclerosis Risk in Communities (ARIC) Study 
Atherosclerosis  2012;222(1):135-137.
OBJECTIVE
We evaluated whether the addition of carotid intima media thickness and plaque (CIMT-P), and, a single nucleotide polymorphism on chromosome 9p21 (9p21) together improve coronary heart disease (CHD) risk prediction in the ARIC study.
METHODS
Ten year CHD risk was estimated using the ARIC coronary risk score (ACRS) alone and in combination with CIMT-P and 9p21 individually and together in White participants (n=9338). Area under the receiver operating characteristic curve (AUC), model calibration, net reclassification index (NRI), integrated discrimination index (IDI) and number of individuals reclassified were estimated.
RESULTS
The AUC of the ACRS, ACRS+9p21, ACRS+CIMT-P and ACRS+CIMT-P+9p21 models were 0.748, 0.751, 0.763 and 0.766 respectively. The percentage of individuals reclassified, model calibration, NRI and IDI improved when CIMT-P and 9p21 were added to the ACRS only model (see manuscript).
CONCLUSION
Addition of 9p21 allele information to CIMT-P minimally improves CHD risk prediction in whites in the ARIC study.
doi:10.1016/j.atherosclerosis.2012.01.028
PMCID: PMC3334435  PMID: 22349088
Carotid intima media thickness; Plaque; 9p21; Risk prediction; Coronary heart disease
13.  Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women's Health Initiative SHARe Study 
Human Molecular Genetics  2011;21(6):1419-1432.
Several genome-wide studies have identified loci associated with reproductive traits, such as ages of menarche and menopause, in women of European ancestry. In this study, we investigated the relevance of these loci in minority US Hispanic women. We utilized data from 3468 women who were genotyped as a part of the Women's Health Initiative SNP Health Association Resource. We replicated associations of eight loci (LRP18, LIN28B, CENPW, INHBA, TMEM38B, ZNF483, NFAT5 and OLFM2) with age at menarche, and of two loci (MCM8 and BRSK1/TMEM150B) with age at menopause. The MCM8 locus was also associated with early menopause risk. Three loci (CENPW, MCM8 and BRSK1/TMEM150B) were associated with the length of reproductive lifespan. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in minority US Hispanic women.
doi:10.1093/hmg/ddr570
PMCID: PMC3284121  PMID: 22131368
14.  Exploring the genetic basis of chronic periodontitis: a genome-wide association study 
Human Molecular Genetics  2013;22(11):2312-2324.
Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age—62 years, moderate CP—43% and severe CP—17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10−6) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)—NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28–1.73, P = 3.5 × 10−7))]; moderate CP (n = 2293)—NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24–1.59, P = 7.5 × 10−8), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52–2.65, P = 8.2 × 10−7). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10−9) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.
doi:10.1093/hmg/ddt065
PMCID: PMC3652417  PMID: 23459936
15.  Heritability and Preliminary Genome-Wide Linkage Analysis of Arsenic Metabolites in Urine 
Environmental Health Perspectives  2013;121(3):345-351.
Background: Arsenic (III) methyltransferase (AS3MT) has been related to urine arsenic metabolites in association studies. Other genes might also play roles in arsenic metabolism and excretion.
Objective: We evaluated genetic determinants of urine arsenic metabolites in American Indian adults from the Strong Heart Study (SHS).
Methods: We evaluated heritability of urine arsenic metabolites [percent inorganic arsenic (%iAs), percent monomethylarsonate (%MMA), and percent dimethylarsinate (%DMA)] in 2,907 SHS participants with urine arsenic measurements and at least one relative within the cohort. We conducted a preliminary linkage analysis in a subset of 487 participants with available genotypes on approximately 400 short tandem repeat markers using a general pedigree variance component approach for localizing quantitative trait loci (QTL).
Results: The medians (interquartile ranges) for %iAs, %MMA, and %DMA were 7.7% (5.4–10.7%), 13.6% (10.5–17.1%), and 78.4% (72.5–83.1%), respectively. The estimated heritability was 53% for %iAs, 50% for %MMA, and 59% for %DMA. After adjustment for sex, age, smoking, body mass index, alcohol consumption, region, and total urine arsenic concentrations, LOD [logarithm (to the base of 10) of the odds] scores indicated suggestive evidence for genetic linkage with QTLs influencing urine arsenic metabolites on chromosomes 5 (LOD = 2.03 for %iAs), 9 (LOD = 2.05 for %iAs and 2.10 for %MMA), and 11 (LOD = 1.94 for %iAs). A peak for %DMA on chromosome 10 within 2 Mb of AS3MT had an LOD of 1.80.
Conclusions: This population-based family study in American Indian communities supports a genetic contribution to variation in the distribution of arsenic metabolites in urine and, potentially, the involvement of genes other than AS3MT.
doi:10.1289/ehp.1205305
PMCID: PMC3621197  PMID: 23322787
American Indians; arsenic metabolism; arsenic species; determinants; heritability; linkage scan; Strong Heart Study
16.  Genotype Imputation of Metabochip SNPs Using a Study-Specific Reference Panel of ~4,000 Haplotypes in African Americans From the Women’s Health Initiative 
Genetic epidemiology  2012;36(2):107-117.
Genetic imputation has become standard practice in modern genetic studies. However, several important issues have not been adequately addressed including the utility of study-specific reference, performance in admixed populations, and quality for less common (minor allele frequency [MAF] 0.005–0.05) and rare (MAF < 0.005) variants. These issues only recently became addressable with genome-wide association studies (GWAS) follow-up studies using dense genotyping or sequencing in large samples of non-European individuals. In this work, we constructed a study-specific reference panel of 3,924 haplotypes using African Americans in the Women’s Health Initiative (WHI) genotyped on both the Metabochip and the Affymetrix 6.0 GWAS platform. We used this reference panel to impute into 6,459 WHI SNP Health Association Resource (SHARe) study subjects with only GWAS genotypes. Our analysis confirmed the imputation quality metric Rsq (estimated r2, specific to each SNP) as an effective post-imputation filter. We recommend different Rsq thresholds for different MAF categories such that the average (across SNPs) Rsq is above the desired dosage r2 (squared Pearson correlation between imputed and experimental genotypes).With a desired dosage r2 of 80%, 99.9% (97.5%, 83.6%, 52.0%, 20.5%) of SNPs with MAF > 0.05 (0.03–0.05, 0.01–0.03, 0.005–0.01, and 0.001–0.005) passed the post-imputation filter. The average dosage r2 for these SNPs is 94.7%, 92.1%, 89.0%, 83.1%, and 79.7%, respectively. These results suggest that for African Americans imputation of Metabochip SNPs from GWAS data, including low frequency SNPs with MAF 0.005–0.05, is feasible and worthwhile for power increase in downstream association analysis provided a sizable reference panel is available.
doi:10.1002/gepi.21603
PMCID: PMC3410659  PMID: 22851474
genotype imputation; Metabochip; internal reference; African Americans; rare variants
17.  A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study 
PLoS Genetics  2013;9(1):e1003171.
Genetic variants in intron 1 of the fat mass– and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI–associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646–kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3×10−6) had not been highlighted in previous studies. While rs56137030was correlated at r2>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
Author Summary
Genetic variants within the fat mass– and obesity-associated (FTO) gene are associated with increased risk of obesity. To better understand which specific genetic variant(s) in this genetic region is associated with obesity risk, we attempt to genotype or impute all known genetic variants in the region and test for association with body mass index as a measurement of obesity in over 20,000 African Americans. We identified 29 potential candidate variants, of which one variant (rs1421085) is a particularly interesting candidate for future functional follow-up studies. Our example shows the powerful approach of studying a large African American population, substantially reducing the number of possible functional variants compared with European descent populations.
doi:10.1371/journal.pgen.1003171
PMCID: PMC3547789  PMID: 23341774
18.  Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study 
BMC Medical Genetics  2013;14:6.
Background
Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.
Methods
As part of the ‘Population Architecture using Genomics and Epidemiology (PAGE)’ Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.
Results
We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, pinteraction = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5x10-5), vs. former/never smokers (β = 0.006, p = 0.05, pinteraction = 0.08).
Conclusions
These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.
Clinical Trial Registration
NCT00000611
doi:10.1186/1471-2350-14-6
PMCID: PMC3564691  PMID: 23311614
Obesity; Body mass index; Genome-wide association study; Genetic risk factor; Smoking interactions; Genetic epidemiology
19.  The case-only independence assumption: associations between genetic polymorphisms and smoking among controls in two population-based studies 
The independence assumption for a case-only analysis of statistical interaction, i. e. that genetic (G) and environmental exposures (E) are not associated in the source population, is often checked in surrogate populations. Few studies have examined G-E association in empirical data, particularly in controls from population-based studies, the type of controls expected to provide the most valid surrogate estimates of G-E association. We used controls from two population-based case-control studies to evaluate G-E independence for 43 selected genetic polymorphisms and smoking behavior. The odds ratio (ORz) was used to estimate G-E association and, therefore, the magnitude of bias introduced into the case-only odds ratio (COR). Odds ratios of moderate magnitude [mmORz], defined as ORz≤0.7 or ORz≥1.4, were found at least one of the six smoking measures (ever, former, current, cig/day, years smoked, pack-years) for 45% and 59% of the SNPs examined in the control groups of two independently conducted North Carolina studies, respectively. Consequently, case-only estimates of G-E interaction in the context of a multiplicative benchmark would be biased for these SNPs and smoking measures. MmORzs were found more often for smoking amount than smoking status. We recommend that a stand-alone case-only study should only be conducted when G-E independence can be verified for each polymorphism and exposure metric with population-specific data. Our results suggest that ORz is specific to each underlying population rather than an estimate of a ‘universal’ ORz for that SNP and smoking measure. Further, misspecification of smoking is likely to introduce bias into the COR.
PMCID: PMC3508536  PMID: 23205185
Case-only; controls; gene-environment interaction; genetic polymorphisms; smoking
20.  Joint Effects of Alcohol Consumption and Polymorphisms in Alcohol and Oxidative Stress Metabolism Genes on Risk of Head and Neck Cancer 
Background
Single nucleotide polymorphisms (SNPs) in alcohol metabolism genes are associated with squamous cell carcinoma of the head and neck (SCCHN), and may influence cancer risk in conjunction with alcohol. Genetic variation in the oxidative stress pathway may impact the carcinogenic effect of reactive oxygen species produced by ethanol metabolism. We hypothesized that alcohol interacts with these pathways to affect SCCHN incidence.
Methods
Interview and genotyping data for 64 SNPs were obtained from 2552 European- and African-American subjects (1227 cases, 1325 controls) from the Carolina Head and Neck Cancer Epidemiology study, a population-based case-control study of SCCHN conducted in North Carolina from 2002–2006. We estimated odds ratios and 95% confidence intervals for SNPs and haplotypes, adjusting for age, sex, race, and duration of cigarette smoking. P-values were adjusted for multiple testing using Bonferroni correction.
Results
Two SNPs were associated with SCCHN risk: ADH1B rs1229984 A allele (OR=0.7, 95%CI=0.6–0.9) and ALDH2 rs2238151 C allele (OR=1.2, 95%CI=1.1–1.4). Three were associated with sub-site tumors: ADH1B rs17028834 C allele (larynx, OR=1.5, 95%CI=1.1–2.0), SOD2 rs4342445 A allele (oral cavity, OR=1.3, 95%CI=1.1–1.6), and SOD2 rs5746134 T allele (hypopharynx, OR=2.1, 95%CI=1.2–3.7). Four SNPs in alcohol metabolism genes interacted additively with alcohol consumption: ALDH2 rs2238151, ADH1B rs1159918, ADH7 rs1154460, and CYP2E1 rs2249695. No alcohol interactions were found for oxidative stress SNPs.
Conclusions and Impact
Previously unreported associations of SNPs in ALDH2, CYP2E1, GPX2, SOD1, and SOD2 with SCCHN and sub-site tumors provide evidence that alterations in alcohol and oxidative stress pathways influence SCCHN carcinogenesis, and warrant further investigation.
doi:10.1158/1055-9965.EPI-11-0649
PMCID: PMC3210881  PMID: 21940907
Head and Neck Neoplasms; Head and Neck Neoplasms/epidemiology; Gene-environment interaction; Alcohol Drinking/metabolism; Oxidative Stress
21.  ADIPOQ, ADIPOR1, and ADIPOR2 Polymorphisms in Relation to Serum Adiponectin Levels and Body Mass Index in Black and White Women 
Obesity (Silver Spring, Md.)  2011;19(10):2053-2062.
Adiponectin is an adipose-secreted protein with influence on several physiologic pathways including those related to insulin sensitivity, inflammation, and atherogenesis. Adiponectin levels are highly heritable and several single nucleotide polymorphisms (SNPs) in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined in relation to circulating adiponectin levels and obesity phenotypes, but despite differences in adiponectin levels and obesity prevalence by race, few studies have included black participants. Using cross-sectional interview data and blood samples collected from 990 black and 977 white women enrolled in the Southern Community Cohort Study from 2002 to 2006, we examined 25 SNPs in ADIPOQ, 19 in ADIPOR1, and 27 in ADIPOR2 in relation to serum adiponectin levels and body mass index (BMI) using race-stratified linear regression models adjusted for age and percentage African ancestry. SNP rs17366568 in ADIPOQ was significantly associated with serum adiponectin levels in white women only (adjusted mean adiponectin levels = 15.9 for G/G genotype, 13.7 for A/G, and 9.3 for A/A, p=0.00036). No other SNPs were associated with adiponectin or BMI among blacks or whites. Because adiponectin levels as well as obesity are highly heritable and vary by race but associations with polymorphisms in the ADIPOQ, ADIPOR1, and ADIPOR2 genes have been few in this and other studies, future work including large populations from diverse racial groups is needed to detect additional genetic variants that influence adiponectin and BMI.
doi:10.1038/oby.2010.346
PMCID: PMC3474141  PMID: 21273992
Adiponectin; obesity; genetics; African Americans
22.  A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium 
Human Molecular Genetics  2011;20(17):3525-3534.
Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50 000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2 000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16 324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12–13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors.
doi:10.1093/hmg/ddr264
PMCID: PMC3153310  PMID: 21676895
23.  Chocolate Consumption is Inversely Associated with Prevalent Coronary Heart Disease: The National Heart, Lung, and Blood Institute Family Heart Study 
Background and Aims
Epidemiologic studies have suggested beneficial effects of flavonoids on cardiovascular disease. Cocoa and particularly dark chocolate are rich in flavonoids and recent studies have demonstrated blood pressure lowering effects of dark chocolate. However, limited data are available on the association of chocolate consumption and the risk of coronary heart disease (CHD). We sought to examine the association between chocolate consumption and prevalent CHD.
Methods
We studied in a cross-sectional design 4,970 participants aged 25 to 93 years who participated in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Chocolate intake was assessed through a semi-quantitative food frequency questionnaire. We used generalized estimating equations to estimate adjusted odds ratios.
Results
Compared to subjects who did not report any chocolate intake, odds ratios (95% CI) for CHD were 1.01 (0.76-1.37), 0.74 (0.56-0.98), and 0.43 (0.28-0.67) for subjects consuming 1-3 times/month, 1-4 times/week, and 5+ times/week, respectively (p for trend <0.0001) adjusting for age, sex, family CHD risk group, energy intake, education, non-chocolate candy intake, linolenic acid intake, smoking, alcohol intake, exercise, and fruit and vegetables. Consumption of non-chocolate candy was associated with a 49% higher prevalence of CHD comparing 5+/week vs. 0/week [OR=1.49 (0.96-2.32)].
Conclusions
These data suggest that consumption of chocolate is inversely related with prevalent CHD in a general population.
doi:10.1016/j.clnu.2010.08.005
PMCID: PMC3039704  PMID: 20858571
epidemiology; carbohydrate; nutrition; cardiovascular disease
24.  A Bivariate Genome-Wide Approach to Metabolic Syndrome 
Diabetes  2011;60(4):1329-1339.
OBJECTIVE
The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS.
RESEARCH DESIGN AND METHODS
Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected.
RESULTS
Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure.
CONCLUSIONS
Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
doi:10.2337/db10-1011
PMCID: PMC3064107  PMID: 21386085
25.  Interaction of FTO and physical activity level on adiposity in African-American and European American adults: The ARIC Study 
Obesity (Silver Spring, Md.)  2011;19(9):1866-1872.
Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations.
Methods
Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 on adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity.
Results
rs9939609 was associated with adiposity in all groups other than AA women. The SNPxPA interaction was significant in AA men (p≤0.002 for all traits) and EA men (p≤0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (βlowPA : 5.1 cm, 95% C.I. 2.6-7.5) than high PA (βhighPA: 0.7 cm, 95% C.I. −0.4 – 1.9); p (interaction) = 0.002). The interaction effect was not observed in EA or AA women.
Conclusion
FTO SNP x PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination.
doi:10.1038/oby.2011.131
PMCID: PMC3293392  PMID: 21593801
Genetics; genotype; FTO; obesity; adiposity; BMI; physical activity; exercise; African-American; interaction; environment

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