Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study
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{"title"=>"Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study", "type"=>"journal", "authors"=>[{"first_name"=>"Frances M.K.", "last_name"=>"Williams", "scopus_author_id"=>"8059345500"}, {"first_name"=>"Serena", "last_name"=>"Scollen", "scopus_author_id"=>"7801641421"}, {"first_name"=>"Dandan", "last_name"=>"Cao", "scopus_author_id"=>"55277555400"}, {"first_name"=>"Yasin", "last_name"=>"Memari", "scopus_author_id"=>"27467538400"}, {"first_name"=>"Craig L.", "last_name"=>"Hyde", "scopus_author_id"=>"15842252300"}, {"first_name"=>"Baohong", "last_name"=>"Zhang", "scopus_author_id"=>"55878075300"}, {"first_name"=>"Benjamin", "last_name"=>"Sidders", "scopus_author_id"=>"17136200800"}, {"first_name"=>"Daniel", "last_name"=>"Ziemek", "scopus_author_id"=>"24077744800"}, {"first_name"=>"Yujian", "last_name"=>"Shi", "scopus_author_id"=>"51665719300"}, {"first_name"=>"Juliette", "last_name"=>"Harris", "scopus_author_id"=>"36652521500"}, {"first_name"=>"Ian", "last_name"=>"Harrow", "scopus_author_id"=>"56616144400"}, {"first_name"=>"Brian", "last_name"=>"Dougherty", "scopus_author_id"=>"56613044000"}, {"first_name"=>"Anders", "last_name"=>"Malarstig", "scopus_author_id"=>"12769910000"}, {"first_name"=>"Robert", "last_name"=>"McEwen", "scopus_author_id"=>"7004905397"}, {"first_name"=>"Joel C.", "last_name"=>"Stephens", "scopus_author_id"=>"55547218400"}, {"first_name"=>"Ketan", "last_name"=>"Patel", "scopus_author_id"=>"36091870500"}, {"first_name"=>"Cristina", "last_name"=>"Menni", "scopus_author_id"=>"25622426300"}, {"first_name"=>"So Youn", "last_name"=>"Shin", "scopus_author_id"=>"37098955800"}, {"first_name"=>"Dylan", "last_name"=>"Hodgkiss", "scopus_author_id"=>"52463784200"}, {"first_name"=>"Gabriela", "last_name"=>"Surdulescu", "scopus_author_id"=>"8959669800"}, {"first_name"=>"Wen", "last_name"=>"He", "scopus_author_id"=>"55547614100"}, {"first_name"=>"Xin", "last_name"=>"Jin", "scopus_author_id"=>"26652540300"}, {"first_name"=>"Stephen B.", "last_name"=>"McMahon", "scopus_author_id"=>"56741596500"}, {"first_name"=>"Nicole", "last_name"=>"Soranzo", "scopus_author_id"=>"55800239500"}, {"first_name"=>"Sally", "last_name"=>"John", "scopus_author_id"=>"35354065700"}, {"first_name"=>"Jun", "last_name"=>"Wang", "scopus_author_id"=>"55586914400"}, {"first_name"=>"Tim D.", "last_name"=>"Spector", "scopus_author_id"=>"35351391300"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-84872021031", "sgr"=>"84872021031", "pui"=>"368067340", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"23284290", "doi"=>"10.1371/journal.pgen.1003095"}, "id"=>"678539b5-4c72-3048-bbd8-a844da06316b", "abstract"=>"Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10(-4)). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.", "link"=>"http://www.mendeley.com/research/genes-contributing-pain-sensitivity-normal-population-exome-sequencing-study", "reader_count"=>77, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>6, "Librarian"=>1, "Researcher"=>17, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>3, "Student > Master"=>11, "Other"=>2, "Student > Bachelor"=>3, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>8}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>6, "Librarian"=>1, "Researcher"=>17, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>3, "Student > Master"=>11, "Other"=>2, "Student > Bachelor"=>3, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>8}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Biochemistry, Genetics and Molecular Biology"=>5, "Nursing and Health Professions"=>2, "Mathematics"=>1, "Medicine and Dentistry"=>25, "Agricultural and Biological Sciences"=>29, "Neuroscience"=>1, "Physics and Astronomy"=>1, "Psychology"=>6, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>25}, "Neuroscience"=>{"Neuroscience"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>29}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>6}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>2, "United Kingdom"=>2, "Spain"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/520133"], "description"=>"<p>Schematic showing number of subjects in TUK1 (top row) and TUK2 (bottom row) having nonsynonymous SNVs within the <i>GZMM</i> gene, with novel variants in black and those described in dbSNP in green. Subject counts in blue are for pain insensitive subjects and in red, pain sensitive. Squares represent homozygous and ovals heterozygous mutations. Exons are shown as dark cylinders, UTRs pale grey rectangles and introns dotted line.</p>", "links"=>[], "tags"=>["public health and epidemiology"], "article_id"=>190594, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.g002", "stats"=>{"downloads"=>7, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNVs_identified_in_gene_GZMM_/190594", "title"=>"SNVs identified in gene <i>GZMM</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-20 00:09:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/520221"], "description"=>"<p>Causal reasoning uses directed molecular interactions to work upstream from the genes in this study (green) to identify regulators such as angiotensin II (blue) that have a causally correct regulatory role for a significant number of input genes. Correctness is determined by giving each input gene a direction of effect. Here, we presumed a loss of function (e.g. down regulation in activity) to all of our genes. Angiotensin II has direct causal connections to 12 of the genes from our 138, which can be increased to 30 if one intermediary node is allowed in the network (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003095#pgen.1003095.s001\" target=\"_blank\">Figure S1</a>). Distribution of novel rare variants identified according to minor allele frequency in a) TUK1 and b) TUK2 datasets.</p>", "links"=>[], "tags"=>["angiotensin", "ii", "was", "causal", "reasoning", "138", "genes"], "article_id"=>190678, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Angiotensin_II_regulatory_network_was_identified_by_causal_reasoning_from_138_genes_associated_with_pain_sensitivity_/190678", "title"=>"The Angiotensin II regulatory network was identified by causal reasoning from 138 genes associated with pain sensitivity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-20 00:11:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/520436"], "description"=>"<p>The number of SNVs detected is shown according to their functional consequences, for the TUK1 and TUK2 samples.</p>", "links"=>[], "tags"=>["snvs", "tuk1", "tuk2"], "article_id"=>190893, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.t002", "stats"=>{"downloads"=>4, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Details_of_the_SNVs_identified_in_TUK1_and_TUK2_samples_/190893", "title"=>"Details of the SNVs identified in TUK1 and TUK2 samples.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-20 00:14:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/520504"], "description"=>"<p>Category of significance (“very high” “High”,“Medium”) as defined below:</p>*<p>represents known pseudogene; Chr chromosome.</p><p>“High” p<0.00044 (based on p-value which reaches genome-wide significance if replicated, based on gene counts); “Very High” means “High” plus the merged data is more significant than by combining TUK1 and TUK2 p-values (implying synergy of direction); “Medium” is p<0.001.</p>", "links"=>[], "tags"=>["methods", "gene-centric", "variant"], "article_id"=>190962, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.t003", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genes_associated_with_heat_pain_sensitivity_using_six_methods_of_gene_centric_variant_burden_analysis_/190962", "title"=>"Genes associated with heat pain sensitivity using six methods of gene-centric variant burden analysis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-20 00:16:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/520364"], "description"=>"<p>The mean (standard deviation) is shown for the TUK1 and TUK2 samples.</p><p>N represents sample size; BMI, body mass index; HPT, heat pain threshold; HPST, heat pain suprathreshold.</p>", "links"=>[], "tags"=>["individuals", "tuk1", "tuk2"], "article_id"=>190835, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.t001", "stats"=>{"downloads"=>6, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_the_individuals_in_the_TUK1_and_TUK2_samples_/190835", "title"=>"Characteristics of the individuals in the TUK1 and TUK2 samples.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-20 00:13:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/520303"], "description"=>"<p>Causal reasoning <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003095#pgen.1003095-Chindelevitch1\" target=\"_blank\">[11]</a> uses a large curated database of directed regulatory molecular interactions to identify the most plausible upstream regulators of a gene set with a proposed directionality (eg. down-regulated). We considered the 138 genes identified to contain loss of function mutations. One regulatory pathway (angiotensin II) is significant after correction for multiple testing when considering directionality (Correctness p) as well as when ignoring directionality of regulation (Enrichment p).</p><p>The sign (−/+) after the regulator's name indicates the loss (−) or gain (+) of activity required to explain the loss of function mutations.</p><p>Enrichment p-value indicates the significance of the number of connections apparent in our data compared to the total number of connections.</p><p>Correctness p-value also accounts for the regulatory direction (+/−) and indicates the significance of the hypothesis as a regulator.</p>", "links"=>[], "tags"=>["causal"], "article_id"=>190774, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.t004", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pathways_identified_by_causal_reasoning_/190774", "title"=>"Pathways identified by causal reasoning.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-12-20 00:12:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/519972"], "description"=>"<p>Quantile–quantile plots are shown for: (a) AMELIA, (b) CCRaVAT, (c) fixed filter test, minor allele frequency <0.05, (d) Madsen-Browning with polyphen weights, (e) Han and Pan aSumtest, (f) SSU, sum-of-squares test (Han and Pan).</p>", "links"=>[], "tags"=>["plots", "variant"], "article_id"=>190429, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003095.g001", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantile_8211_quantile_plots_for_the_six_different_variant_burden_analysis_methods_/190429", "title"=>"Quantile–quantile plots for the six different variant burden analysis methods.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-12-20 00:07:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/283919", "https://ndownloader.figshare.com/files/283964", "https://ndownloader.figshare.com/files/284005", "https://ndownloader.figshare.com/files/284061", "https://ndownloader.figshare.com/files/284120"], "description"=>"<div><p>Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10<sup>−4</sup>). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.</p> </div>", "links"=>[], "tags"=>["genes", "contributing", "exome", "sequencing", "study"], "article_id"=>115966, "categories"=>["Biotechnology"], "users"=>["Frances M. K. Williams", "Serena Scollen", "Dandan Cao", "Yasin Memari", "Craig L. Hyde", "Baohong Zhang", "Benjamin Sidders", "Daniel Ziemek", "Yujian Shi", "Juliette Harris", "Ian Harrow", "Brian Dougherty", "Anders Malarstig", "Robert McEwen", "Joel C. Stephens", "Ketan Patel", "Cristina Menni", "So-Youn Shin", "Dylan Hodgkiss", "Gabriela Surdulescu", "Wen He", "Xin Jin", "Stephen B. McMahon", "Nicole Soranzo", "Sally John", "Jun Wang", "Tim D. Spector"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003095.s001", "https://dx.doi.org/10.1371/journal.pgen.1003095.s002", "https://dx.doi.org/10.1371/journal.pgen.1003095.s003", "https://dx.doi.org/10.1371/journal.pgen.1003095.s004", "https://dx.doi.org/10.1371/journal.pgen.1003095.s005"], "stats"=>{"downloads"=>32, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genes_Contributing_to_Pain_Sensitivity_in_the_Normal_Population_An_Exome_Sequencing_Study__/115966", "title"=>"Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-12-20 01:39:26"}

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Relative Metric

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