A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)
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{"title"=>"A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)", "type"=>"journal", "authors"=>[{"first_name"=>"David", "last_name"=>"Melzer"}, {"first_name"=>"John R. B.", "last_name"=>"Perry"}, {"first_name"=>"Dena", "last_name"=>"Hernandez"}, {"first_name"=>"Anna-Maria", "last_name"=>"Corsi"}, {"first_name"=>"Kara", "last_name"=>"Stevens"}, {"first_name"=>"Ian", "last_name"=>"Rafferty"}, {"first_name"=>"Fulvio", "last_name"=>"Lauretani"}, {"first_name"=>"Anna", "last_name"=>"Murray"}, {"first_name"=>"J. Raphael", "last_name"=>"Gibbs"}, {"first_name"=>"Giuseppe", "last_name"=>"Paolisso"}, {"first_name"=>"Sajjad", "last_name"=>"Rafiq"}, {"first_name"=>"Javier", "last_name"=>"Simon-Sanchez"}, {"first_name"=>"Hana", "last_name"=>"Lango"}, {"first_name"=>"Sonja", "last_name"=>"Scholz"}, {"first_name"=>"Michael N.", "last_name"=>"Weedon"}, {"first_name"=>"Sampath", "last_name"=>"Arepalli"}, {"first_name"=>"Neil", "last_name"=>"Rice"}, {"first_name"=>"Nicole", "last_name"=>"Washecka"}, {"first_name"=>"Alison", "last_name"=>"Hurst"}, {"first_name"=>"Angela", "last_name"=>"Britton"}, {"first_name"=>"William", "last_name"=>"Henley"}, {"first_name"=>"Joyce", "last_name"=>"van de Leemput"}, {"first_name"=>"Rongling", "last_name"=>"Li"}, {"first_name"=>"Anne B.", "last_name"=>"Newman"}, {"first_name"=>"Greg", "last_name"=>"Tranah"}, {"first_name"=>"Tamara", "last_name"=>"Harris"}, {"first_name"=>"Vijay", "last_name"=>"Panicker"}, {"first_name"=>"Colin", "last_name"=>"Dayan"}, {"first_name"=>"Amanda", "last_name"=>"Bennett"}, {"first_name"=>"Mark I.", "last_name"=>"McCarthy"}, {"first_name"=>"Aimo", "last_name"=>"Ruokonen"}, {"first_name"=>"Marjo-Riitta", "last_name"=>"Jarvelin"}, {"first_name"=>"Jack", "last_name"=>"Guralnik"}, {"first_name"=>"Stefania", "last_name"=>"Bandinelli"}, {"first_name"=>"Timothy M.", "last_name"=>"Frayling"}, {"first_name"=>"Andrew", "last_name"=>"Singleton"}, {"first_name"=>"Luigi", "last_name"=>"Ferrucci"}], "year"=>2008, "source"=>"PLoS Genetics", "identifiers"=>{"pmid"=>"18464913", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "issn"=>"1553-7404", "doi"=>"10.1371/journal.pgen.1000072"}, "id"=>"0e6138e3-2c15-34f9-9f02-a462e20832a6", "abstract"=>"There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.", "link"=>"http://www.mendeley.com/research/genomewide-association-study-identifies-protein-quantitative-trait-loci-pqtls-2", "reader_count"=>100, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>44, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Other"=>4, "Student > Master"=>7, "Student > Bachelor"=>2, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Researcher"=>44, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>27, "Student > Postgraduate"=>4, "Other"=>4, "Student > Master"=>7, "Student > Bachelor"=>2, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>12, "Mathematics"=>2, "Agricultural and Biological Sciences"=>63, "Medicine and Dentistry"=>15, "Arts and Humanities"=>1, "Psychology"=>2, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>15}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>63}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>12}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>3}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>4, "China"=>1, "United Kingdom"=>6, "Italy"=>1, "France"=>2, "Spain"=>1}, "group_count"=>8}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/459296", "https://ndownloader.figshare.com/files/459350", "https://ndownloader.figshare.com/files/459407", "https://ndownloader.figshare.com/files/459488", "https://ndownloader.figshare.com/files/459533", "https://ndownloader.figshare.com/files/459619", "https://ndownloader.figshare.com/files/459657", "https://ndownloader.figshare.com/files/459795", "https://ndownloader.figshare.com/files/459836"], "description"=>"<div><p>There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – <em>cis</em> effects, and elsewhere in the genome – <em>trans</em> effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight <em>Cis</em> effects, including variants in or near the <em>IL6R</em> (p = 1.8×10<sup>−57</sup>), <em>CCL4L1</em> (p = 3.9×10<sup>−21</sup>), <em>IL18</em> (p = 6.8×10<sup>−13</sup>), <em>LPA</em> (p = 4.4×10<sup>−10</sup>), <em>GGT1</em> (p = 1.5×10<sup>−7</sup>), <em>SHBG</em> (p = 3.1×10<sup>−7</sup>), <em>CRP</em> (p = 6.4×10<sup>−6</sup>) and <em>IL1RN</em> (p = 7.3×10<sup>−6</sup>) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (<em>IL6R</em>), altered secretion rates of different sized proteins <em>(LPA),</em> variation in gene copy number <em>(CCL4L1)</em> and altered transcription <em>(GGT1)</em>. We identified one novel <em>trans</em> effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10<sup>−40</sup>), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in <em>cis</em> locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.</p></div>", "links"=>[], "tags"=>["genome-wide", "identifies", "quantitative", "loci"], "article_id"=>150482, "categories"=>["Chemistry", "Genetics", "Biochemistry", "Medicine"], "users"=>["David Melzer", "John R. B. Perry", "Dena Hernandez", "Anna-Maria Corsi", "Kara Stevens", "Ian Rafferty", "Fulvio Lauretani", "Anna Murray", "J. Raphael Gibbs", "Giuseppe Paolisso", "Sajjad Rafiq", "Javier Simón-Sánchez", "Hana Lango", "Sonja Scholz", "Michael N. Weedon", "Sampath Arepalli", "Neil Rice", "Nicole Washecka", "Alison Hurst", "Angela Britton", "William Henley", "Joyce van de Leemput", "Rongling Li", "Anne B. Newman", "Greg Tranah", "Tamara Harris", "Vijay Panicker", "Colin Dayan", "Amanda Bennett", "Mark I. McCarthy", "Aimo Ruokonen", "Marjo-Riitta Jarvelin", "Jack Guralnik", "Stefania Bandinelli", "Timothy M. Frayling", "Andrew Singleton", "Luigi Ferrucci"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000072.s001", "https://dx.doi.org/10.1371/journal.pgen.1000072.s002", "https://dx.doi.org/10.1371/journal.pgen.1000072.s003", "https://dx.doi.org/10.1371/journal.pgen.1000072.s004", "https://dx.doi.org/10.1371/journal.pgen.1000072.s005", "https://dx.doi.org/10.1371/journal.pgen.1000072.s006", "https://dx.doi.org/10.1371/journal.pgen.1000072.s007", "https://dx.doi.org/10.1371/journal.pgen.1000072.s008", "https://dx.doi.org/10.1371/journal.pgen.1000072.s009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Genome_Wide_Association_Study_Identifies_Protein_Quantitative_Trait_Loci_pQTLs_/150482", "title"=>"A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-05-09 00:08:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/931904"], "description"=>"<p>For each SNP the X axis represents the distance in base pairs from either the 5′ or 3′ end of the gene. If SNPs occur within the gene, either in introns or exons, they are given a distance of zero. SNPs in <i>IL6R</i> <1×10<sup>−25</sup> not shown.</p>", "links"=>[], "tags"=>["snps", "1megabase"], "article_id"=>602293, "categories"=>["Chemistry", "Genetics", "Biochemistry", "Medicine"], "users"=>["David Melzer", "John R. B. Perry", "Dena Hernandez", "Anna-Maria Corsi", "Kara Stevens", "Ian Rafferty", "Fulvio Lauretani", "Anna Murray", "J. Raphael Gibbs", "Giuseppe Paolisso", "Sajjad Rafiq", "Javier Simón-Sánchez", "Hana Lango", "Sonja Scholz", "Michael N. Weedon", "Sampath Arepalli", "Neil Rice", "Nicole Washecka", "Alison Hurst", "Angela Britton", "William Henley", "Joyce van de Leemput", "Rongling Li", "Anne B. Newman", "Greg Tranah", "Tamara Harris", "Vijay Panicker", "Colin Dayan", "Amanda Bennett", "Mark I. McCarthy", "Aimo Ruokonen", "Marjo-Riitta Jarvelin", "Jack Guralnik", "Stefania Bandinelli", "Timothy M. Frayling", "Andrew Singleton", "Luigi Ferrucci"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000072.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_SNPs_1Megabase_from_each_cis_gene_/602293", "title"=>"Association of SNPs 1Megabase from each <i>cis</i> gene.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-09 00:38:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/932025"], "description"=>"<p>X axis shows the distance on the relevant chromosome. Left hand Y axis shows the −log10 p values and right hand Y axis shows the recombination rate as calculated from HapMap data.</p>", "links"=>[], "tags"=>["genotype"], "article_id"=>602427, "categories"=>["Chemistry", "Genetics", "Biochemistry", "Medicine"], "users"=>["David Melzer", "John R. B. Perry", "Dena Hernandez", "Anna-Maria Corsi", "Kara Stevens", "Ian Rafferty", "Fulvio Lauretani", "Anna Murray", "J. Raphael Gibbs", "Giuseppe Paolisso", "Sajjad Rafiq", "Javier Simón-Sánchez", "Hana Lango", "Sonja Scholz", "Michael N. Weedon", "Sampath Arepalli", "Neil Rice", "Nicole Washecka", "Alison Hurst", "Angela Britton", "William Henley", "Joyce van de Leemput", "Rongling Li", "Anne B. Newman", "Greg Tranah", "Tamara Harris", "Vijay Panicker", "Colin Dayan", "Amanda Bennett", "Mark I. McCarthy", "Aimo Ruokonen", "Marjo-Riitta Jarvelin", "Jack Guralnik", "Stefania Bandinelli", "Timothy M. Frayling", "Andrew Singleton", "Luigi Ferrucci"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000072.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cis_genotype_effects_/602427", "title"=>"<i>Cis</i> genotype effects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-09 00:40:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/932159"], "description"=>"<p>Basic characteristics of the InCHIANTI study population.</p>", "links"=>[], "tags"=>["inchianti"], "article_id"=>602549, "categories"=>["Chemistry", "Genetics", "Biochemistry", "Medicine"], "users"=>["David Melzer", "John R. B. Perry", "Dena Hernandez", "Anna-Maria Corsi", "Kara Stevens", "Ian Rafferty", "Fulvio Lauretani", "Anna Murray", "J. Raphael Gibbs", "Giuseppe Paolisso", "Sajjad Rafiq", "Javier Simón-Sánchez", "Hana Lango", "Sonja Scholz", "Michael N. Weedon", "Sampath Arepalli", "Neil Rice", "Nicole Washecka", "Alison Hurst", "Angela Britton", "William Henley", "Joyce van de Leemput", "Rongling Li", "Anne B. Newman", "Greg Tranah", "Tamara Harris", "Vijay Panicker", "Colin Dayan", "Amanda Bennett", "Mark I. McCarthy", "Aimo Ruokonen", "Marjo-Riitta Jarvelin", "Jack Guralnik", "Stefania Bandinelli", "Timothy M. Frayling", "Andrew Singleton", "Luigi Ferrucci"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000072.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Basic_characteristics_of_the_InCHIANTI_study_population_/602549", "title"=>"Basic characteristics of the InCHIANTI study population.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-09 00:42:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/932249"], "description"=>"<p>MAF = minor allele frequency, SNP = single nucleotide polymorphism and represents the best p value. Distance represents the distance from the gene or location within gene.</p><p>GC P represents the p value corrected for inflation factors but not multiple testing. Mean trait values are back transformed values from transformed means, except for LPA where frequencies of genotypes in the low (first value) and high (second value) level groups are given. 11 = common hom, 12 = het, 22 = minor allele homozygote. Perm = Permutation.</p><p>P values based on 100,000 region wide (gene +-300 kb) permutations for <i>cis</i> effects and 10,000 genome-wide permutations for <i>trans</i> effects (“<” indicates the observed p value did not occur in these numbers of permutations). <sup>*</sup>Further analysis shows that this signal is driven by a SNP, rs1799941, in partial LD with rs6761 – see text.</p>", "links"=>[], "tags"=>["biochemistry/protein chemistry", "biochemistry/transcription and translation", "cardiovascular disorders", "diabetes and endocrinology", "genetics and genomics/complex traits", "genetics and genomics/functional genomics", "genetics and genomics/gene expression", "genetics and genomics/genetics of disease", "genetics and genomics/genome projects", "genetics and genomics/physiogenomics"], "article_id"=>602628, "categories"=>["Chemistry", "Genetics", "Biochemistry", "Medicine"], "users"=>["David Melzer", "John R. B. Perry", "Dena Hernandez", "Anna-Maria Corsi", "Kara Stevens", "Ian Rafferty", "Fulvio Lauretani", "Anna Murray", "J. Raphael Gibbs", "Giuseppe Paolisso", "Sajjad Rafiq", "Javier Simón-Sánchez", "Hana Lango", "Sonja Scholz", "Michael N. Weedon", "Sampath Arepalli", "Neil Rice", "Nicole Washecka", "Alison Hurst", "Angela Britton", "William Henley", "Joyce van de Leemput", "Rongling Li", "Anne B. Newman", "Greg Tranah", "Tamara Harris", "Vijay Panicker", "Colin Dayan", "Amanda Bennett", "Mark I. McCarthy", "Aimo Ruokonen", "Marjo-Riitta Jarvelin", "Jack Guralnik", "Stefania Bandinelli", "Timothy M. Frayling", "Andrew Singleton", "Luigi Ferrucci"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000072.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Details_of_Cis_and_trans_effects_/602628", "title"=>"Details of <i>Cis</i> and <i>trans</i> effects.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-09 00:43:48"}

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Relative Metric

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