A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose
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{"title"=>"A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose", "type"=>"journal", "authors"=>[{"first_name"=>"Fumihiko", "last_name"=>"Takeuchi", "scopus_author_id"=>"7103237031"}, {"first_name"=>"Ralph", "last_name"=>"McGinnis", "scopus_author_id"=>"7003755585"}, {"first_name"=>"Stephane", "last_name"=>"Bourgeois", "scopus_author_id"=>"8098017100"}, {"first_name"=>"Chris", "last_name"=>"Barnes", "scopus_author_id"=>"24764733700"}, {"first_name"=>"Niclas", "last_name"=>"Eriksson", "scopus_author_id"=>"15072587100"}, {"first_name"=>"Nicole", "last_name"=>"Soranzo", "scopus_author_id"=>"55800239500"}, {"first_name"=>"Pamela", "last_name"=>"Whittaker", "scopus_author_id"=>"56804575900"}, {"first_name"=>"Venkatesh", "last_name"=>"Ranganath", "scopus_author_id"=>"21741481400"}, {"first_name"=>"Vasudev", "last_name"=>"Kumanduri", "scopus_author_id"=>"12776775800"}, {"first_name"=>"William", "last_name"=>"McLaren", "scopus_author_id"=>"16686734100"}, {"first_name"=>"Lennart", "last_name"=>"Holm", "scopus_author_id"=>"24080378700"}, {"first_name"=>"Jonatan", "last_name"=>"Lindh", "scopus_author_id"=>"7003857375"}, {"first_name"=>"Anders", "last_name"=>"Rane", "scopus_author_id"=>"7102519032"}, {"first_name"=>"Mia", "last_name"=>"Wadelius", "scopus_author_id"=>"6603005522"}, {"first_name"=>"Panos", "last_name"=>"Deloukas", "scopus_author_id"=>"7003287098"}], "year"=>2009, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-63449117825", "pui"=>"354404871", "pmid"=>"19300499", "issn"=>"15537390", "isbn"=>"1553-7404 (Electronic)", "doi"=>"10.1371/journal.pgen.1000433", "sgr"=>"63449117825"}, "id"=>"eb6ae9b8-f78e-3512-92af-86e327b8feb6", "abstract"=>"We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7)) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3) in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78)) at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31)) emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (p = 8.3 x 10(-10)) that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.", "link"=>"http://www.mendeley.com/research/genomewide-association-study-confirms-vkorc1-cyp2c9-cyp4f2-principal-genetic-determinants-warfarin-d", "reader_count"=>231, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>17, "Librarian"=>1, "Researcher"=>49, "Student > Doctoral Student"=>12, "Student > Ph. D. Student"=>42, "Student > Postgraduate"=>18, "Student > Master"=>30, "Other"=>7, "Student > Bachelor"=>39, "Lecturer"=>3, "Lecturer > Senior Lecturer"=>5, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>17, "Librarian"=>1, "Researcher"=>49, "Student > Doctoral Student"=>12, "Student > Ph. D. Student"=>42, "Student > Postgraduate"=>18, "Student > Master"=>30, "Other"=>7, "Student > Bachelor"=>39, "Lecturer"=>3, "Lecturer > Senior Lecturer"=>5, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>11, "Agricultural and Biological Sciences"=>111, "Business, Management and Accounting"=>1, "Veterinary Science and Veterinary Medicine"=>1, "Chemical Engineering"=>1, "Computer Science"=>4, "Decision Sciences"=>1, "Earth and Planetary Sciences"=>1, "Engineering"=>1, "Environmental Science"=>3, "Biochemistry, Genetics and Molecular Biology"=>20, "Mathematics"=>2, "Medicine and Dentistry"=>61, "Design"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>7, "Psychology"=>3, "Social Sciences"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>61}, "Social Sciences"=>{"Social Sciences"=>2}, "Decision Sciences"=>{"Decision Sciences"=>1}, "Psychology"=>{"Psychology"=>3}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>11}, "Environmental Science"=>{"Environmental Science"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>7}, "Chemical Engineering"=>{"Chemical Engineering"=>1}, "Design"=>{"Design"=>1}, "Engineering"=>{"Engineering"=>1}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>111}, "Computer Science"=>{"Computer Science"=>4}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>20}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Colombia"=>1, "United States"=>6, "Japan"=>3, "United Kingdom"=>1, "Portugal"=>2, "Switzerland"=>1, "Russia"=>1, "Spain"=>2, "Canada"=>1, "Netherlands"=>1, "Pakistan"=>1, "Brazil"=>1, "Mexico"=>3, "Italy"=>1, "France"=>1, "Chile"=>1, "Germany"=>2}, "group_count"=>14}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/904446"], "description"=>"<p>Horizontal axis shows SNP location and vertical axis is −log10(p-value) for each SNP tested by univariate regression (A) or multivariate regression (B). Red dots and red lettering show SNPs and implicated genes with p-values beyond the genome-wide significance threshold (1.5×10<sup>−7</sup>) which is denoted by a horizontal line. (A) Univariate regression shows genome-wide significant association to SNPs clustering near the warfarin drug target <i>VKORC1</i> (e.g., <i>P</i> = 5.4×10<sup>−78</sup>, rs9923231) and near the warfarin-metabolizing gene <i>CYP2C9</i> (<i>P</i> = 4.5×10<sup>−17</sup> for non-synonymous <i>*3 SNP</i> rs1057910, <i>P</i> = 8.8×10<sup>−13</sup> for non-synonymous <i>*2 SNP</i> rs1799853, <i>P</i> = 3.1×10<sup>−31</sup> for <i>*2*3</i> “composite” SNP rs4917639). (B) Multivariate regression adjusting for the contributions of <i>VKORC1</i> and <i>CYP2C9</i> had greater power than univariate regression and detected genome-wide significant association to the <i>CYP4F2</i> gene (<i>P</i> = 8.3×10<sup>−10</sup>, non-synonymous SNP rs2108622).</p>", "links"=>[], "tags"=>["GWAS", "snp", "tested", "warfarin"], "article_id"=>574881, "categories"=>["Mathematics", "Genetics", "Pharmacology"], "users"=>["Fumihiko Takeuchi", "Ralph McGinnis", "Stephane Bourgeois", "Chris Barnes", "Niclas Eriksson", "Nicole Soranzo", "Pamela Whittaker", "Venkatesh Ranganath", "Vasudev Kumanduri", "William McLaren", "Lennart Holm", "Jonatan Lindh", "Anders Rane", "Mia Wadelius", "Panos Deloukas"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000433.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_P_values_for_each_GWAS_SNP_tested_for_association_with_warfarin_dose_/574881", "title"=>"P-values for each GWAS SNP tested for association with warfarin dose.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-03-20 01:21:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/447056", "https://ndownloader.figshare.com/files/447118", "https://ndownloader.figshare.com/files/447173", "https://ndownloader.figshare.com/files/447188", "https://ndownloader.figshare.com/files/447202", "https://ndownloader.figshare.com/files/447219", "https://ndownloader.figshare.com/files/447227"], "description"=>"<div><p>We report the first genome-wide association study (GWAS) whose sample size (1,053 Swedish subjects) is sufficiently powered to detect genome-wide significance (<em>p</em><1.5×10<sup>−7</sup>) for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold) in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness) or too high (risking severe bleeding). Prior work established that ∼30% of the dose variance is explained by single nucleotide polymorphisms (SNPs) in the warfarin drug target <em>VKORC1</em> and another ∼12% by two non-synonymous SNPs (<em>*2</em>, <em>*3</em>) in the cytochrome P450 warfarin-metabolizing gene <em>CYP2C9</em>. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (<em>p</em><10<sup>−78</sup>) at SNPs clustering near <em>VKORC1</em> and the second lowest p-values (<em>p</em><10<sup>−31</sup>) emanating from <em>CYP2C9</em>. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (<em>VKORC1</em>, <em>CYP2C9</em>, age, gender) and identified a single SNP (rs2108622) with genome-wide significance (<em>p</em> = 8.3×10<sup>−10</sup>) that alters protein coding of the <em>CYP4F2</em> gene. We confirmed this result in 588 additional Swedish patients (<em>p</em><0.0029) and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers explaining at least 1.5% of dose variance. These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose.</p></div>", "links"=>[], "tags"=>["genome-wide", "confirms", "determinants", "warfarin"], "article_id"=>148123, "categories"=>["Mathematics", "Genetics", "Pharmacology"], "users"=>["Fumihiko Takeuchi", "Ralph McGinnis", "Stephane Bourgeois", "Chris Barnes", "Niclas Eriksson", "Nicole Soranzo", "Pamela Whittaker", "Venkatesh Ranganath", "Vasudev Kumanduri", "William McLaren", "Lennart Holm", "Jonatan Lindh", "Anders Rane", "Mia Wadelius", "Panos Deloukas"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000433.s001", "https://dx.doi.org/10.1371/journal.pgen.1000433.s002", "https://dx.doi.org/10.1371/journal.pgen.1000433.s003", "https://dx.doi.org/10.1371/journal.pgen.1000433.s004", "https://dx.doi.org/10.1371/journal.pgen.1000433.s005", "https://dx.doi.org/10.1371/journal.pgen.1000433.s006", "https://dx.doi.org/10.1371/journal.pgen.1000433.s007"], "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A_Genome_Wide_Association_Study_Confirms_VKORC1_CYP2C9_and_CYP4F2_as_Principal_Genetic_Determinants_of_Warfarin_Dose/148123", "title"=>"A Genome-Wide Association Study Confirms <em>VKORC1</em>, <em>CYP2C9</em>, and <em>CYP4F2</em> as Principal Genetic Determinants of Warfarin Dose", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-03-20 02:15:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/904680"], "description"=>"a<p>Linear regression on warfarin dose was calculated for the 1,053 GWAS subjects.</p>", "links"=>[], "tags"=>["snps", "tested", "univariate", "regression"], "article_id"=>575115, "categories"=>["Mathematics", "Genetics", "Pharmacology"], "users"=>["Fumihiko Takeuchi", "Ralph McGinnis", "Stephane Bourgeois", "Chris Barnes", "Niclas Eriksson", "Nicole Soranzo", "Pamela Whittaker", "Venkatesh Ranganath", "Vasudev Kumanduri", "William McLaren", "Lennart Holm", "Jonatan Lindh", "Anders Rane", "Mia Wadelius", "Panos Deloukas"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000433.t001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_p_value_of_SNPs_tested_by_univariate_regression_or_multiple_regression_with_progressive_addition_of_known_dose_predictors_a_/575115", "title"=>"Association (<i>p</i>-value) of SNPs tested by univariate regression or multiple regression with progressive addition of known dose predictors<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-20 01:25:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/904563"], "description"=>"a<p>Power calculations assumed a sample size of 1,053 subjects and significance level of 1.5E-7 as employed in our GWAS.</p>", "links"=>[], "tags"=>["dose-altering", "snp", "variance", "predictors", "regression"], "article_id"=>574997, "categories"=>["Mathematics", "Genetics", "Pharmacology"], "users"=>["Fumihiko Takeuchi", "Ralph McGinnis", "Stephane Bourgeois", "Chris Barnes", "Niclas Eriksson", "Nicole Soranzo", "Pamela Whittaker", "Venkatesh Ranganath", "Vasudev Kumanduri", "William McLaren", "Lennart Holm", "Jonatan Lindh", "Anders Rane", "Mia Wadelius", "Panos Deloukas"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000433.t003", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Power_to_detect_a_dose_altering_SNP_as_a_function_of_its_contribution_to_dose_variance_R_2_and_adjustment_by_other_predictors_in_the_multiple_regression_model_a_/574997", "title"=>"Power to detect a dose-altering SNP as a function of its contribution to dose variance (<i>R</i><sup>2</sup>) and adjustment by other predictors in the multiple regression model<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-20 01:23:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/904615"], "description"=>"a<p>In parenthesis are major/minor allele, and minor allele frequency.</p>b<p>Effect of individual predictor on dose is indicated by regression coefficient and 95% confidence interval, proportion of explained variance (<i>R</i><sup>2</sup>) and <i>P</i>-value.</p>c<p>Association in same direction as GWAS was assessed by a one-tailed test.</p>", "links"=>[], "tags"=>["regression", "warfarin", "replication"], "article_id"=>575057, "categories"=>["Mathematics", "Genetics", "Pharmacology"], "users"=>["Fumihiko Takeuchi", "Ralph McGinnis", "Stephane Bourgeois", "Chris Barnes", "Niclas Eriksson", "Nicole Soranzo", "Pamela Whittaker", "Venkatesh Ranganath", "Vasudev Kumanduri", "William McLaren", "Lennart Holm", "Jonatan Lindh", "Anders Rane", "Mia Wadelius", "Panos Deloukas"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000433.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Multiple_regression_analysis_of_warfarin_dose_in_the_GWAS_replication_and_combined_panels_/575057", "title"=>"Multiple regression analysis of warfarin dose in the GWAS, replication and combined panels.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-03-20 01:24:17"}

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  • {"unique-ip"=>"50", "full-text"=>"61", "pdf"=>"18", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"25", "full-text"=>"35", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"23", "full-text"=>"20", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"29", "full-text"=>"34", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"1", "cited-by"=>"1", "year"=>"2019", "month"=>"10"}

Relative Metric

{"start_date"=>"2009-01-01T00:00:00Z", "end_date"=>"2009-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Evolutionary biology", "average_usage"=>[422, 680, 795, 921, 1012, 1113, 1216, 1296, 1396, 1468, 1545, 1617, 1701, 1770, 1872, 1951, 2013, 2071, 2118, 2171, 2251, 2290, 2345, 2401, 2471, 2528, 2576, 2634, 2702, 2776, 2840, 2897, 2962, 3046, 3101, 3141, 3222, 3292, 3342, 3436, 3483, 3533, 3604, 3662, 3804, 3843, 3919, 3979, 4043, 4119, 4170, 4198, 4285, 4336, 4402, 4455, 4522, 4607, 4649, 4668, 4713]}, {"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[334, 613, 751, 863, 964, 1078, 1181, 1270, 1358, 1443, 1536, 1616, 1690, 1768, 1826, 1902, 1969, 2031, 2095, 2149, 2202, 2258, 2305, 2349, 2417, 2482, 2541, 2598, 2662, 2720, 2768, 2832, 2897, 2947, 2998, 3058, 3121, 3175, 3235, 3292, 3368, 3442, 3507, 3563, 3621, 3676, 3736, 3802, 3852, 3922, 3977, 4025, 4071, 4141, 4199, 4258, 4316, 4376, 4422, 4467, 4518]}, {"subject_area"=>"/Medicine and health sciences/Pharmaceutics", "average_usage"=>[383, 606, 753, 875, 970, 1073, 1195, 1283, 1367, 1455, 1557, 1631, 1730, 1807, 1861, 1926, 1991, 2036, 2133, 2190, 2227, 2273, 2326, 2386, 2456, 2523, 2583, 2637, 2755, 2806, 2877, 2938, 3022, 3101, 3141, 3201, 3254, 3306, 3358, 3396, 3467, 3517, 3568, 3675, 3716, 3757, 3799, 3847, 3896, 3937, 3989, 4042, 4089, 4167, 4226, 4265, 4351, 4425, 4497, 4573, 4648, 4730]}, {"subject_area"=>"/Physical sciences/Mathematics", "average_usage"=>[390, 657, 764, 869, 966, 1052, 1148, 1251, 1329, 1410, 1469, 1529, 1603, 1663, 1723, 1784, 1858, 1929, 1995, 2054, 2103, 2155, 2202, 2268, 2305, 2346, 2398, 2449, 2484, 2546, 2590, 2652, 2726, 2763, 2825, 2879, 2926, 2985, 3054, 3114, 3160, 3243, 3304, 3389, 3466, 3519, 3561, 3631, 3679, 3731, 3805, 3859, 3907, 3944, 3994, 4076, 4150, 4202, 4229, 4275, 4344, 4373]}]}

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