Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee
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{"title"=>"Genome-wide gene-environment study identifies glutamate receptor gene grin2a as a parkinson's disease modifier gene via interaction with coffee", "type"=>"journal", "authors"=>[{"first_name"=>"Taye H.", "last_name"=>"Hamza", "scopus_author_id"=>"23034357000"}, {"first_name"=>"Honglei", "last_name"=>"Chen", "scopus_author_id"=>"35331605500"}, {"first_name"=>"Erin M.", "last_name"=>"Hill-Burns", "scopus_author_id"=>"35208294400"}, {"first_name"=>"Shannon L.", "last_name"=>"Rhodes", "scopus_author_id"=>"7102851221"}, {"first_name"=>"Jennifer", "last_name"=>"Montimurro", "scopus_author_id"=>"8905660400"}, {"first_name"=>"Denise M.", "last_name"=>"Kay", "scopus_author_id"=>"8947960700"}, {"first_name"=>"Albert", "last_name"=>"Tenesa", "scopus_author_id"=>"8247573400"}, {"first_name"=>"Victoria I.", "last_name"=>"Kusel", "scopus_author_id"=>"36241904700"}, {"first_name"=>"Patricia", "last_name"=>"Sheehan", "scopus_author_id"=>"51161898500"}, {"first_name"=>"Muthukrishnan", "last_name"=>"Eaaswarkhanth", "scopus_author_id"=>"21233734400"}, {"first_name"=>"Dora", "last_name"=>"Yearout", "scopus_author_id"=>"14631351300"}, {"first_name"=>"Ali", "last_name"=>"Samii", "scopus_author_id"=>"7005553590"}, {"first_name"=>"John W.", "last_name"=>"Roberts", "scopus_author_id"=>"55482981500"}, {"first_name"=>"Pinky", "last_name"=>"Agarwal", "scopus_author_id"=>"57201522863"}, {"first_name"=>"Yvette", "last_name"=>"Bordelon", "scopus_author_id"=>"16063140900"}, {"first_name"=>"Yikyung", "last_name"=>"Park", "scopus_author_id"=>"9939659000"}, {"first_name"=>"Liyong", "last_name"=>"Wang", "scopus_author_id"=>"34976013600"}, {"first_name"=>"Jianjun", "last_name"=>"Gao", "scopus_author_id"=>"7404475242"}, {"first_name"=>"Jeffery M.", "last_name"=>"Vance", "scopus_author_id"=>"7201366505"}, {"first_name"=>"Kenneth S.", "last_name"=>"Kendler", "scopus_author_id"=>"35396760800"}, {"first_name"=>"Silviu Alin", "last_name"=>"Bacanu", "scopus_author_id"=>"6602873682"}, {"first_name"=>"William K.", "last_name"=>"Scott", "scopus_author_id"=>"7403054141"}, {"first_name"=>"Beate", "last_name"=>"Ritz", "scopus_author_id"=>"7003571709"}, {"first_name"=>"John", "last_name"=>"Nutt", "scopus_author_id"=>"7101742343"}, {"first_name"=>"Stewart A.", "last_name"=>"Factor", "scopus_author_id"=>"7101901383"}, {"first_name"=>"Cyrus P.", "last_name"=>"Zabetian", "scopus_author_id"=>"6602931331"}, {"first_name"=>"Haydeh", "last_name"=>"Payami", "scopus_author_id"=>"7005484083"}], "year"=>2011, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"362471758", "sgr"=>"80052328932", "pmid"=>"21876681", "scopus"=>"2-s2.0-80052328932", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "doi"=>"10.1371/journal.pgen.1002237", "issn"=>"15537390"}, "id"=>"d1df2f70-d65b-3ef0-816d-cfaf1549fede", "abstract"=>"Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df) = 10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that \"Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers\" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR = 0.41, P = 3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.", "link"=>"http://www.mendeley.com/research/genomewide-geneenvironment-study-identifies-glutamate-receptor-gene-grin2a-parkinsons-disease-modifi", "reader_count"=>140, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>11, "Student > Doctoral Student"=>6, "Researcher"=>38, "Student > Ph. D. Student"=>26, "Student > Postgraduate"=>5, "Student > Master"=>13, "Other"=>5, "Student > Bachelor"=>22, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>7}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>11, "Student > Doctoral Student"=>6, "Researcher"=>38, "Student > Ph. D. Student"=>26, "Student > Postgraduate"=>5, "Student > Master"=>13, "Other"=>5, "Student > Bachelor"=>22, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>7}, "reader_count_by_subject_area"=>{"Unspecified"=>11, "Agricultural and Biological Sciences"=>71, "Chemistry"=>1, "Computer Science"=>2, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>8, "Nursing and Health Professions"=>2, "Mathematics"=>2, "Medicine and Dentistry"=>30, "Neuroscience"=>7, "Sports and Recreations"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Psychology"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>30}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>3}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>11}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Engineering"=>{"Engineering"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Neuroscience"=>{"Neuroscience"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>71}, "Computer Science"=>{"Computer Science"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}}, "reader_count_by_country"=>{"Austria"=>1, "Netherlands"=>1, "United States"=>5, "Japan"=>1, "Egypt"=>1, "United Kingdom"=>2, "Italy"=>1, "Paraguay"=>1, "Switzerland"=>1, "Germany"=>2, "Spain"=>1}, "group_count"=>9}

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  • {"files"=>["https://ndownloader.figshare.com/files/744510"], "description"=>"<p>See also <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-g002\" target=\"_blank\">Figure 2</a>. Standard GWAS (PD-SNP association, no interaction) was conducted among heavy and light coffee drinkers separately. <i>GRIN2A</i> was most notable only among heavy coffee drinkers. Odds ratio (OR) of 0.41–0.46 suggests that among heavy coffee drinkers, who are known to be at reduced risk for PD, <i>GRIN2A</i> genotypes further modifies risk by over two-fold. As expected due to interaction, <i>GRIN2A</i> did not have a significant effect in light coffee drinkers. This is in contrast to known PD genes which exhibited their effects on PD risk regardless of coffee consumption.</p>", "links"=>[], "tags"=>["was", "GWAS"], "article_id"=>414849, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.t002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GRIN2A_was_the_most_significant_result_in_GWAS_in_heavy_coffee_drinkers_/414849", "title"=>"<i>GRIN2A</i> was the most significant result in GWAS in heavy coffee-drinkers.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-18 01:20:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/744447"], "description"=>"<p>C genotype was associated with reduced risk consistently across studies. rs4998386_TT frequency varied significantly across studies. The a-priori hypothesis for replication that among heavy drinkers <i>GRIN2A</i>_rs4998386_T carriers had a lower risk of PD than <i>GRIN2A</i>_rs4998386_CC was replicated under three conditions: comparing TC to CC (excluding rare and variable TT genotype) shown here, Dominant model (TT+TC vs. CC) and Additive model (TT vs. TC vs CC) shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s007\" target=\"_blank\">Table S3</a>. As predicted from the Discovery phase, genotype had no effect on risk of PD among light coffee drinkers. The joint effects of genotype and coffee showed a significant 59% drop in PD risk in people who had the rs4998386_TC genotype and were heavy drinkers, but little or no effect in other combinations. A formal interaction test demonstrated that the effects of coffee and genotype are dependent on each other. By definition, statistical interaction exists if the joint effect of gene (g) and exposure (e) is significantly different from the product of their individual effects. Interaction OR is the ratio of the OR of disease when g and e are present, divided by the product of the individual OR; i.e., OR<sub>interaction</sub> = OR<sub>g+e</sub>/(OR<sub>g</sub>×OR<sub>e</sub>). (F) Dose-dependent risk reduction by coffee was clear and strong for rs4998386_TC genotype. Analyses were repeated with smoking (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s008\" target=\"_blank\">Table S4</a>) or caffeinated soda/tea (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s009\" target=\"_blank\">Table S5</a>) as additional covariates, results were unchanged.</p><p>*Heterogeneity P: Breslow-Day test statistics to assess between-study heterogeneity conducted for coffee and genotypes and found to be significant only for TT genotype. Analyses were adjusted for sex and age at interview in each dataset, and also for study in the pooled analyses. Expanded analysis including results for individual replication data sets are shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s007\" target=\"_blank\">Table S3</a>.</p>", "links"=>[], "tags"=>["conditioned", "genotype"], "article_id"=>414788, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.t003", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PD_risk_conditioned_on_GRIN2A_genotype_and_coffee_use_/414788", "title"=>"PD risk conditioned on <i>GRIN2A</i> genotype and coffee use.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-18 01:19:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/744653"], "description"=>"<p><i>GRIN2A</i> was the most significant area in both the GWAIS and the GWAS in heavy coffee users. This table shows results that achieved P≤5×10<sup>−8</sup>; for a complete list of all SNPs that achieved P<10<sup>−5</sup> see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s011\" target=\"_blank\">Table S7</a>.</p>", "links"=>[], "tags"=>["GWAS", "genotyped", "imputed"], "article_id"=>414983, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.t004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GWAIS_and_GWAS_results_on_combined_genotyped_and_imputed_data_/414983", "title"=>"GWAIS and GWAS results on combined genotyped and imputed data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-18 01:23:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/744579"], "description"=>"<p>Also see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-g001\" target=\"_blank\">Figure 1</a>. GWAIS analysis was [SNP+SNP*coffee] test with 2 df adjusting for sex, age, PC1 and PC2. The test examines the significance of the SNP main effect and its interaction with coffee, without introducing the significant effect of coffee on PD. Results for <i>GRIN2A</i> were equally significant under Dominant and Additive models. Recessive model had no clear signal (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s001\" target=\"_blank\">Figure S1</a>). Also shown are the results obtained with the same dataset and under the same analytic model for the known PD genes <i>SNCA</i>, <i>MAPT</i> and <i>HLA</i>. <i>SNCA</i> and <i>HLA</i> had reached P<5×10<sup>−8</sup> in our GWAS. The fall in significance in GWAIS is due in part to 1/3 reduction in sample size due to unavailability of coffee data, and also the penalty imposed by the added degree of freedom. <i>GRIN2A</i> did not have a strong main effect to be noticed in GWAS, but in GWAIS, the inclusion of coffee and interaction placed <i>GRIN2A</i> higher than <i>SNCA</i>, <i>HLA</i> and <i>MAPT</i>.</p>", "links"=>[], "tags"=>["was"], "article_id"=>414921, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.t001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GRIN2A_was_the_most_significant_signal_in_GWAIS_/414921", "title"=>"<i>GRIN2A</i> was the most significant signal in GWAIS.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-08-18 01:22:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/744297"], "description"=>"<p>Neither the Manhattan plot (Panel A) nor the QQ plot (Panel B) exhibit evidence of association between <i>GRIN2A</i> and PD among individuals who drink little or no coffee.</p>", "links"=>[], "tags"=>[], "article_id"=>414634, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.g003", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GWAS_in_light_coffee_drinkers_/414634", "title"=>"GWAS in light coffee-drinkers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-18 01:17:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/375399", "https://ndownloader.figshare.com/files/375589", "https://ndownloader.figshare.com/files/375665", "https://ndownloader.figshare.com/files/375712", "https://ndownloader.figshare.com/files/375770", "https://ndownloader.figshare.com/files/375819", "https://ndownloader.figshare.com/files/375861", "https://ndownloader.figshare.com/files/375902", "https://ndownloader.figshare.com/files/375966", "https://ndownloader.figshare.com/files/376004", "https://ndownloader.figshare.com/files/376038"], "description"=>"<div><p>Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in <em>GRIN2A</em>. <em>GRIN2A</em> encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P<sub>2df</sub> = 10<sup>−6</sup>, <em>GRIN2A</em> surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the <em>GRIN2A</em> signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10<sup>−7</sup>) but not in light coffee-drinkers. The <em>a priori</em> Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: OR<sub>Replication</sub> = 0.59, P<sub>Replication</sub> = 10<sup>−3</sup>; OR<sub>Pooled</sub> = 0.51, P<sub>Pooled</sub> = 7×10<sup>−8</sup>. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10<sup>−3</sup>), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10<sup>−13</sup>). Imputation revealed a block of SNPs that achieved P<sub>2df</sub><5×10<sup>−8</sup> in GWAIS, and OR = 0.41, P = 3×10<sup>−8</sup> in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (<em>GRIN2A</em>-related) are being tested in clinical trials for treatment of PD. <em>GRIN2A</em> may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.</p> </div>", "links"=>[], "tags"=>["genome-wide", "gene-environment", "identifies", "glutamate", "receptor", "modifier"], "article_id"=>134130, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002237.s001", "https://dx.doi.org/10.1371/journal.pgen.1002237.s002", "https://dx.doi.org/10.1371/journal.pgen.1002237.s003", "https://dx.doi.org/10.1371/journal.pgen.1002237.s004", "https://dx.doi.org/10.1371/journal.pgen.1002237.s005", "https://dx.doi.org/10.1371/journal.pgen.1002237.s006", "https://dx.doi.org/10.1371/journal.pgen.1002237.s007", "https://dx.doi.org/10.1371/journal.pgen.1002237.s008", "https://dx.doi.org/10.1371/journal.pgen.1002237.s009", "https://dx.doi.org/10.1371/journal.pgen.1002237.s010", "https://dx.doi.org/10.1371/journal.pgen.1002237.s011"], "stats"=>{"downloads"=>49, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genome_Wide_Gene_Environment_Study_Identifies_Glutamate_Receptor_Gene_GRIN2A_as_a_Parkinson_s_Disease_Modifier_Gene_via_Interaction_with_Coffee/134130", "title"=>"Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene <em>GRIN2A</em> as a Parkinson's Disease Modifier Gene via Interaction with Coffee", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-08-18 01:08:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/744129"], "description"=>"<p>Panel A depicts GWAS in heavy coffee drinkers with <i>GRIN2A</i> achieving the lowest P values. The P values in stratified GWAS are for genotyped SNP's main effect on PD risk, adjusted for sex, age, PC1 and PC2. Imputed SNPs (not shown here) achieved P = 3×10<sup>−8</sup> (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-t004\" target=\"_blank\">Table 4</a>). Additive model is shown here; see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s001\" target=\"_blank\">Figure S1</a> for Dominant model. Dominant and additive models yielded similar results for top hits (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-t002\" target=\"_blank\">Table 2</a>). Panel B is the QQ plot for heavy coffee drinkers where the observed P values (red line) are plotted against the expected P values under no association (straight black line). The plots were made first by including all SNPs (red), then excluding <i>SNCA</i>, <i>HLA</i> and <i>MAPT</i> (green) and finally by excluding <i>GRIN2A</i> (blue). Unlike the QQ plot for GWAIS, the effects of <i>SNCA</i>, <i>HLA</i> and <i>MAPT</i> are unnoticeable. The only deviation is seen at the extreme <10<sup>−5</sup> which is primarily due to <i>GRIN2A</i>.</p>", "links"=>[], "tags"=>[], "article_id"=>414468, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.g002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GWAS_in_heavy_coffee_drinkers_/414468", "title"=>"GWAS in heavy coffee-drinkers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-18 01:14:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/743994"], "description"=>"<p>Panel A depicts the Manhattan plot for the GWAIS (joint test of association and interaction with coffee, 2df, adjusted for sex, age, PC1 and PC2). The novel spike on chromosome 16 corresponds to 12 <i>GRIN2A</i> SNPs that were genotyped. Imputed SNPs achieved P<sub>2df</sub><5×10<sup>−8</sup> (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-t004\" target=\"_blank\">Table 4</a>). Additive model is shown here, Dominant and Recessive are in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen.1002237.s001\" target=\"_blank\">Figure S1</a>. Dominant and Additive models yielded similar results for top hits (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002237#pgen-1002237-t001\" target=\"_blank\">Table 1</a>). Panel B is the QQ plot where the observed P values (red line) are plotted against the expected P values under no association (straight black line). The plots were made first by including all genotyped SNPs (red), then excluding those in the <i>SNCA</i>, <i>HLA</i> and <i>MAPT</i> regions (green) and finally by excluding <i>GRIN2A</i> (blue).</p>", "links"=>[], "tags"=>["qq"], "article_id"=>414334, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Taye H. Hamza", "Honglei Chen", "Erin M. Hill-Burns", "Shannon L. Rhodes", "Jennifer Montimurro", "Denise M. Kay", "Albert Tenesa", "Victoria I. Kusel", "Patricia Sheehan", "Muthukrishnan Eaaswarkhanth", "Dora Yearout", "Ali Samii", "John W. Roberts", "Pinky Agarwal", "Yvette Bordelon", "Yikyung Park", "Liyong Wang", "Jianjun Gao", "Jeffery M. Vance", "Kenneth S. Kendler", "Silviu-Alin Bacanu", "William K. Scott", "Beate Ritz", "John Nutt", "Stewart A. Factor", "Cyrus P. Zabetian", "Haydeh Payami"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002237.g001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Manhattan_Plot_and_QQ_Plot_of_GWAIS_/414334", "title"=>"Manhattan Plot and QQ Plot of GWAIS.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-08-18 01:12:14"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"16", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"24", "full-text"=>"29", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"11", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"26", "full-text"=>"20", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"13", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
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  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"20", "full-text"=>"25", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"20", "full-text"=>"17", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

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