Dataset Information

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

ABSTRACT: In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

SUBMITTER: Loley C

PROVIDER: S-EPMC5059659 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

Loley Christina C Alver Maris M Assimes Themistocles L TL Bjonnes Andrew A Goel Anuj A Gustafsson Stefan S Hernesniemi Jussi J Hopewell Jemma C JC Kanoni Stavroula S Kleber Marcus E ME Lau King Wai KW Lu Yingchang Y Lyytikäinen Leo-Pekka LP Nelson Christopher P CP Nikpay Majid M Qu Liming L Salfati Elias E Scholz Markus M Tukiainen Taru T Willenborg Christina C Won Hong-Hee HH Zeng Lingyao L Zhang Weihua W Anand Sonia S SS Beutner Frank F Bottinger Erwin P EP Clarke Robert R Dedoussis George G Do Ron R Esko Tõnu T Eskola Markku M Farrall Martin M Gauguier Dominique D Giedraitis Vilmantas V Granger Christopher B CB Hall Alistair S AS Hamsten Anders A Hazen Stanley L SL Huang Jie J Kähönen Mika M Kyriakou Theodosios T Laaksonen Reijo R Lind Lars L Lindgren Cecilia C Magnusson Patrik K E PK Marouli Eirini E Mihailov Evelin E Morris Andrew P AP Nikus Kjell K Pedersen Nancy N Rallidis Loukianos L Salomaa Veikko V Shah Svati H SH Stewart Alexandre F R AF Thompson John R JR Zalloua Pierre A PA Chambers John C JC Collins Rory R Ingelsson Erik E Iribarren Carlos C Karhunen Pekka J PJ Kooner Jaspal S JS Lehtimäki Terho T Loos Ruth J F RJ März Winfried W McPherson Ruth R Metspalu Andres A Reilly Muredach P MP Ripatti Samuli S Sanghera Dharambir K DK Thiery Joachim J Watkins Hugh H Deloukas Panos P Kathiresan Sekar S Samani Nilesh J NJ Schunkert Heribert H Erdmann Jeanette J König Inke R IR

Scientific reports 20161012

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role ...[more]

PMID: 27731410

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Project description:BACKGROUND:Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS:We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS:Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS:We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

Project description:Coronary artery disease (CAD) is a complex disorder with genetic and environmental influences. Genome-wide association studies (GWAS) have identified over 300 genomic loci associated with disease risk. However, identifying the functional variants within these loci has been limited in large part due to linkage disequilibrium. This represents a critical step in understanding the molecular mechanisms underlying disease risk. To identify and prioritize candidate causal CAD-associated variants, we performed lentivirus-based massively parallel reporter assays (lentiMPRAs) in primary vascular smooth muscle cells (SMCs), which play significant roles in atherosclerosis, the underlying cause of CAD. We tested 25892 CAD-associated variants for their allele-specific enhancer activity in quiescent and proliferative SMCs, modeling healthy and disease conditions. We identified 122 candidate variants showing significant enhancer activity and differences in reporter gene expression between risk and non-risk alleles. We also identified 23 variants showing condition-biased allelic imbalance and 41 variants showing sex-biased allelic imbalance. We further functionally characterized 25892 variants by performing CUT&RUN assays to identify variants in enhancer and promoter regions of SMCs. By integrating the results of these experiments, we identified a credible set of 49 CAD-associated variants in functionally relevant regions. Furthermore, by comparing these identified variants with our previously obtained expression quantitative trait loci (eQTL) data, 27 of these 49 variants were associated with SMC gene expression levels. Finally, we performed CRISPRi experiments on 8 variants comprising 9 variant-gene pairs, rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF), rs4627080 (NRIP3), to confirm their regulatory potential of nearby gene expression. Taken together, our results comprehensively fine-map the causal variants that confer increased risk of CAD through their effects on vascular smooth muscle cells.

Dataset Information

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

Publications

No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.

Similar Datasets

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