Dataset Information

Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.

ABSTRACT: Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

SUBMITTER: Chen LS

PROVIDER: S-EPMC3387741 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.

Chen Li-Shiun LS Saccone Nancy L NL Culverhouse Robert C RC Bracci Paige M PM Chen Chien-Hsiun CH Dueker Nicole N Han Younghun Y Huang Hongyan H Jin Guangfu G Kohno Takashi T Ma Jennie Z JZ Przybeck Thomas R TR Sanders Alan R AR Smith Jennifer A JA Sung Yun Ju YJ Wenzlaff Angie S AS Wu Chen C Yoon Dankyu D Chen Ying-Ting YT Cheng Yu-Ching YC Cho Yoon Shin YS David Sean P SP Duan Jubao J Eaton Charles B CB Furberg Helena H Goate Alison M AM Gu Dongfeng D Hansen Helen M HM Hartz Sarah S Hu Zhibin Z Kim Young Jin YJ Kittner Steven J SJ Levinson Douglas F DF Mosley Thomas H TH Payne Thomas J TJ Rao D C DC Rice John P JP Rice Treva K TK Schwantes-An Tae-Hwi TH Shete Sanjay S SS Shi Jianxin J Spitz Margaret R MR Sun Yan V YV Tsai Fuu-Jen FJ Wang Jen C JC Wrensch Margaret R MR Xian Hong H Gejman Pablo V PV He Jiang J Hunt Steven C SC Kardia Sharon L SL Li Ming D MD Lin Dongxin D Mitchell Braxton D BD Park Taesung T Schwartz Ann G AG Shen Hongbing H Wiencke John K JK Wu Jer-Yuarn JY Yokota Jun J Amos Christopher I CI Bierut Laura J LJ

Genetic epidemiology 20120501 4

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European anc ...[more]

PMID: 22539395

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Project description:BACKGROUND/OBJECTIVES:Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS:To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15?945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS:Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS:Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Project description:Background: Differences in levels of gene expression among individuals are an important source of phenotypic variation within populations. Recent microarray studies have revealed that expression variation is abundant in many species, including Drosophila melanogaster. However, previous expression surveys in this species generally focused on a small number of laboratory strains established from derived populations. Thus, these studies were not ideal for population genetic analyses. Results: We surveyed gene expression variation in adult males of 16 D. melanogaster strains from two natural populations, including an ancestral African population and a derived European population. Levels of expression polymorphism were nearly equal in the two populations, but a higher number of differences was detected when comparing strains between populations. Expression variation was greatest for genes associated with few molecular functions or biological processes, as well as those expressed predominantly in males. Our analysis also identified genes that differed in expression level between the European and African populations, which may be candidates for adaptive regulatory evolution. Genes involved in flight musculature and fatty acid metabolism were over-represented in the list of candidates. Conclusions: Overall, stabilizing selection appears to be the major force governing gene expression variation within populations. However, positive selection may be responsible for much of the between-population expression divergence. The nature of the genes identified to differ in expression between populations may reveal which traits were important for local adaptation to the European and African environments. We used dual channel microarrays to compare genome-wide expression profiles in adult males from 16 inbred strains derived from two natural populations. In total 80 hybidizations were performed including dye-swaps. The hybridization scheme consisted of a balanced loop design, which allowed an unbiased comparison of relative expression levels within and between populations.

Dataset Information

Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.

Publications

Smoking and genetic risk variation across populations of European, Asian, and African American ancestry--a meta-analysis of chromosome 15q25.

Similar Datasets

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