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Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

ABSTRACT: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

SUBMITTER: Myocardial Infarction Genetics Consortium

PROVIDER: S-EPMC2681011 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

Kathiresan Sekar S Voight Benjamin F BF Purcell Shaun S Musunuru Kiran K Ardissino Diego D Mannucci Pier M PM Anand Sonia S Engert James C JC Samani Nilesh J NJ Schunkert Heribert H Erdmann Jeanette J Reilly Muredach P MP Rader Daniel J DJ Morgan Thomas T Spertus John A JA Stoll Monika M Girelli Domenico D McKeown Pascal P PP Patterson Chris C CC Siscovick David S DS O'Donnell Christopher J CJ Elosua Roberto R Peltonen Leena L Salomaa Veikko V Schwartz Stephen M SM Melander Olle O Altshuler David D Ardissino Diego D Merlini Pier Angelica PA Berzuini Carlo C Bernardinelli Luisa L Peyvandi Flora F Tubaro Marco M Celli Patrizia P Ferrario Maurizio M Fetiveau Raffaela R Marziliano Nicola N Casari Giorgio G Galli Michele M Ribichini Flavio F Rossi Marco M Bernardi Francesco F Zonzin Pietro P Piazza Alberto A Mannucci Pier M PM Schwartz Stephen M SM Siscovick David S DS Yee Jean J Friedlander Yechiel Y Elosua Roberto R Marrugat Jaume J Lucas Gavin G Subirana Isaac I Sala Joan J Ramos Rafael R Kathiresan Sekar S Meigs James B JB Williams Gordon G Nathan David M DM MacRae Calum A CA O'Donnell Christopher J CJ Salomaa Veikko V Havulinna Aki S AS Peltonen Leena L Melander Olle O Berglund Goran G Voight Benjamin F BF Kathiresan Sekar S Hirschhorn Joel N JN Asselta Rosanna R Duga Stefano S Spreafico Marta M Musunuru Kiran K Daly Mark J MJ Purcell Shaun S Voight Benjamin F BF Purcell Shaun S Nemesh James J Korn Joshua M JM McCarroll Steven A SA Schwartz Stephen M SM Yee Jean J Kathiresan Sekar S Lucas Gavin G Subirana Isaac I Elosua Roberto R Surti Aarti A Guiducci Candace C Gianniny Lauren L Mirel Daniel D Parkin Melissa M Burtt Noel N Gabriel Stacey B SB Samani Nilesh J NJ Thompson John R JR Braund Peter S PS Wright Benjamin J BJ Balmforth Anthony J AJ Ball Stephen G SG Hall Alistair S A Schunkert Heribert H Erdmann Jeanette J Linsel-Nitschke Patrick P Lieb Wolfgang W Ziegler Andreas A König Inke I Hengstenberg Christian C Fischer Marcus M Stark Klaus K Grosshennig Anika A Preuss Michael M Wichmann H-Erich HE Schreiber Stefan S Schunkert Heribert H Samani Nilesh J NJ Erdmann Jeanette J Ouwehand Willem W Hengstenberg Christian C Deloukas Panos P Scholz Michael M Cambien Francois F Reilly Muredach P MP Li Mingyao M Chen Zhen Z Wilensky Robert R Matthai William W Qasim Atif A Hakonarson Hakon H HH Devaney Joe J Burnett Mary-Susan MS Pichard Augusto D AD Kent Kenneth M KM Satler Lowell L Lindsay Joseph M JM Waksman Ron R Knouff Christopher W CW Waterworth Dawn M DM Walker Max C MC Mooser Vincent V Epstein Stephen E SE Rader Daniel J DJ Scheffold Thomas T Berger Klaus K Stoll Monika M Huge Andreas A Girelli Domenico D Martinelli Nicola N Olivieri Oliviero O Corrocher Roberto R Morgan Thomas T Spertus John A JA McKeown Pascal P Patterson Chris C CC Schunkert Heribert H Erdmann Erdmann E Linsel-Nitschke Patrick P Lieb Wolfgang W Ziegler Andreas A König Inke R IR Hengstenberg Christian C Fischer Marcus M Stark Klaus K Grosshennig Anika A Preuss Michael M Wichmann H-Erich HE Schreiber Stefan S Hólm Hilma H Thorleifsson Gudmar G Thorsteinsdottir Unnur U Stefansson Kari K Engert James C JC Do Ron R Xie Changchun C Anand Sonia S Kathiresan Sekar S Ardissino Diego D Mannucci Pier M PM Siscovick David D O'Donnell Christopher J CJ Samani Nilesh J NJ Melander Olle O Elosua Roberto R Peltonen Leena L Salomaa Veikko V Schwartz Stephen M SM Altshuler David D

Nature genetics 20090208 3

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p ...[more]

PMID: 19198609

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Project description:BackgroundThe carcass value of cattle is a function of carcass weight and quality. Given the economic importance of carcass merit to producers, it is routinely included in beef breeding objectives. A detailed understanding of the genetic variants that contribute to carcass merit is useful to maximize the efficiency of breeding for improved carcass merit. The objectives of the present study were two-fold: firstly, to perform genome-wide association analyses of carcass weight, carcass conformation, and carcass fat using copy number variant (CNV) data in a population of 923 Holstein-Friesian, 945 Charolais, and 974 Limousin bulls; and secondly to perform separate association analyses of carcass traits on the same population of cattle using the Log R ratio (LRR) values of 712,555 single nucleotide polymorphisms (SNPs). The LRR value of a SNP is a measure of the signal intensity of the SNP generated during the genotyping process.ResultsA total of 13,969, 3,954, and 2,805 detected CNVs were tested for association with the three carcass traits for the Holstein-Friesian, Charolais, and Limousin, respectively. The copy number of 16 CNVs and the LRR of 34 SNPs were associated with at least one of the three carcass traits in at least one of the three cattle breeds. With the exception of three SNPs, none of the quantitative trait loci detected in the CNV association analyses or the SNP LRR association analyses were also detected using traditional association analyses based on SNP allele counts. Many of the CNVs and SNPs associated with the carcass traits were located near genes related to the structure and function of the spliceosome and the ribosome; in particular, U6 which encodes a spliceosomal subunit and 5S rRNA which encodes a ribosomal subunit.ConclusionsThe present study demonstrates that CNV data and SNP LRR data can be used to detect genomic regions associated with carcass traits in cattle providing information on quantitative trait loci over and above those detected using just SNP allele counts, as is the approach typically employed in genome-wide association analyses.

Project description:Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.

Dataset Information

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

Publications

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

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