Genetic Association Study of Adiposity and Melanocortin-4 Receptor (MC4R) Common Variants: Replication and Functional Characterization of Non-Coding Regions
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{"title"=>"Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: Replication and functional characterization of non-coding regions", "type"=>"journal", "authors"=>[{"first_name"=>"Daniel S.", "last_name"=>"Evans", "scopus_author_id"=>"37060867300"}, {"first_name"=>"Melissa A.", "last_name"=>"Calton", "scopus_author_id"=>"26321359300"}, {"first_name"=>"Mee J.", "last_name"=>"Kim", "scopus_author_id"=>"57199746284"}, {"first_name"=>"Pui Yan", "last_name"=>"Kwok", "scopus_author_id"=>"22976024000"}, {"first_name"=>"Iva", "last_name"=>"Miljkovic", "scopus_author_id"=>"26533175300"}, {"first_name"=>"Tamara", "last_name"=>"Harris", "scopus_author_id"=>"35375662400"}, {"first_name"=>"Annemarie", "last_name"=>"Koster", "scopus_author_id"=>"35237466800"}, {"first_name"=>"Yongmei", "last_name"=>"Liu", "scopus_author_id"=>"35435449700"}, {"first_name"=>"Gregory J.", "last_name"=>"Tranah", "scopus_author_id"=>"6602848494"}, {"first_name"=>"Nadav", "last_name"=>"Ahituv", "scopus_author_id"=>"8510545900"}, {"first_name"=>"Wen Chi", "last_name"=>"Hsueh", "scopus_author_id"=>"7102703659"}, {"first_name"=>"Christian", "last_name"=>"Vaisse", "scopus_author_id"=>"7003456230"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"373143872", "sgr"=>"84901258900", "doi"=>"10.1371/journal.pone.0096805", "scopus"=>"2-s2.0-84901258900", "isbn"=>"1932-6203", "pmid"=>"24820477"}, "id"=>"408aac2a-14b1-348a-a3eb-7930151351d6", "abstract"=>"Common genetic variants 3' of MC4R within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the MC4R gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the MC4R region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3' LD block (closer to MC4R) was significantly associated with multiple adiposity traits, but SNPs in a distal 3' LD block (farther from MC4R) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of MC4R. By considering nucleotide conservation, the significance of association, and proximity to the MC4R gene, we identified a candidate MC4R regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using in vivo enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered MC4R expression.", "link"=>"http://www.mendeley.com/research/genetic-association-study-adiposity-melanocortin4-receptor-mc4r-common-variants-replication-function", "reader_count"=>29, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>3, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>8, "Nursing and Health Professions"=>2, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>4, "Design"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Design"=>{"Design"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1493561"], "description"=>"<p>SNP genotypes from genome-wide Illumina array. In the panel displaying BMI association <i>P</i>-values, circles mark directly genotyped SNPs and triangles mark imputed SNPs. Gray points indicate association <i>P</i>-value >0.05. Red points indicate significant (<i>P</i>-value ≤0.05) associations with BMI. Anchor SNPs colored in blue. Purple circles mark SNP association with <i>MC4R</i> expression in HapMap CEU lymphoblastoid cell lines. In the panels showing trait association and eQTL <i>P</i>-values, the dashed line indicates cut-off value for Bonferroni-corrected <i>P</i>-value ≤0.05. LD heatmap indicates higher <i>r</i><sup>2</sup> measures with darker red colors. Nucleotide conservation between the human and mouse is indicated on the top panel of the figure and was obtained using the VISTA browser.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "bmi", "genotyped", "imputed", "snps", "abc"], "article_id"=>1023392, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_between_BMI_and_genotyped_and_imputed_SNPs_in_white_Health_ABC_participants_/1023392", "title"=>"Association between BMI and genotyped and imputed SNPs in white Health ABC participants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493568"], "description"=>"<p>Alleles listed as reference allele/coded allele. CAF =  coded allele frequency. VAT =  abdominal visceral adipose tissue. SAT =  abdominal subcutaneous adipose tissue.</p>a<p>Additive coding  = rs52820871/I251L, rs2229616/V103I, and rs17782313; dominant coding  = rs11152221; recessive coding  = rs1943225.</p>b<p>Leptin outcome adjusted for percentage of body fat.</p>c<p>Unadjusted <i>P</i>-value. <i>P</i>-values >0.05 shown as NS (not significant).</p><p>*Empirical <i>P</i>-value ≤0.05.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "associations", "adiposity-related", "abc"], "article_id"=>1023399, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.t003", "stats"=>{"downloads"=>3, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNP_associations_with_adiposity_related_traits_in_Health_ABC_white_female_and_white_male_participants_/1023399", "title"=>"SNP associations with adiposity-related traits in Health ABC white female and white male participants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493569"], "description"=>"<p>VAT =  abdominal visceral adipose tissue. SAT =  abdominal subcutaneous adipose tissue.</p><p>*<i>p</i><0.05 between races by t-test for continuous traits and by Chi-squared test for categorical traits.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "abc"], "article_id"=>1023400, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.t001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Health_ABC_participant_characteristics_by_race_/1023400", "title"=>"Health ABC participant characteristics by race.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493567"], "description"=>"<p>Alleles listed as reference allele/coded allele. CAF =  coded allele frequency. VAT =  abdominal visceral adipose tissue. SAT =  abdominal subcutaneous adipose tissue.</p>a<p>Additive coding  = rs52820871/I251L, rs2229616/V103I, and rs17782313; dominant coding  = rs11152221; recessive coding  = rs1943225.</p>b<p>Leptin outcome adjusted for percentage of body fat.</p>c<p>Unadjusted <i>P</i>-value. <i>P</i>-values >0.05 shown as NS (not significant).</p><p>*Empirical <i>P</i>-value ≤0.05.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "associations", "adiposity-related", "abc"], "article_id"=>1023398, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.t002", "stats"=>{"downloads"=>2, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNP_associations_with_adiposity_related_traits_in_Health_ABC_white_participants_/1023398", "title"=>"SNP associations with adiposity-related traits in Health ABC white participants.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493559"], "description"=>"<p>SNP genotypes from custom Illumina Golden Gate array. Gray points indicate association <i>P</i>-value >0.05. Non-gray points indicate significant (<i>P</i>-value ≤0.05) associations with an adiposity trait of the corresponding color in the legend. Leptin* indicates association <i>P</i>-value for leptin adjusted for percent body fat. Dashed line indicates cut-off value for empirical <i>P</i>-value ≤0.05. LD heatmap indicates higher <i>r</i><sup>2</sup> measures with darker red colors.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "associations", "adiposity", "abc"], "article_id"=>1023389, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SNP_associations_in_and_near_MC4R_with_adiposity_in_white_Health_ABC_participants_/1023389", "title"=>"SNP associations in and near <i>MC4R</i> with adiposity in white Health ABC participants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493572", "https://ndownloader.figshare.com/files/1493573", "https://ndownloader.figshare.com/files/1493574", "https://ndownloader.figshare.com/files/1493575", "https://ndownloader.figshare.com/files/1493576", "https://ndownloader.figshare.com/files/1493577", "https://ndownloader.figshare.com/files/1493578", "https://ndownloader.figshare.com/files/1493579", "https://ndownloader.figshare.com/files/1493580", "https://ndownloader.figshare.com/files/1493582"], "description"=>"<div><p>Common genetic variants 3′ of <i>MC4R</i> within two large linkage disequilibrium (LD) blocks spanning 288 kb have been associated with common and rare forms of obesity. This large association region has not been refined and the relevant DNA segments within the association region have not been identified. In this study, we investigated whether common variants in the <i>MC4R</i> gene region were associated with adiposity-related traits in a biracial population-based study. Single nucleotide polymorphisms (SNPs) in the <i>MC4R</i> region were genotyped with a custom array and a genome-wide array and associations between SNPs and five adiposity-related traits were determined using race-stratified linear regression. Previously reported associations between lower BMI and the minor alleles of rs2229616/Val103Ile and rs52820871/Ile251Leu were replicated in white female participants. Among white participants, rs11152221 in a proximal 3′ LD block (closer to <i>MC4R</i>) was significantly associated with multiple adiposity traits, but SNPs in a distal 3′ LD block (farther from <i>MC4R</i>) were not. In a case-control study of severe obesity, rs11152221 was significantly associated. The association results directed our follow-up studies to the proximal LD block downstream of <i>MC4R</i>. By considering nucleotide conservation, the significance of association, and proximity to the <i>MC4R</i> gene, we identified a candidate <i>MC4R</i> regulatory region. This candidate region was sequenced in 20 individuals from a study of severe obesity in an attempt to identify additional variants, and the candidate region was tested for enhancer activity using <i>in vivo</i> enhancer assays in zebrafish and mice. Novel variants were not identified by sequencing and the candidate region did not drive reporter gene expression in zebrafish or mice. The identification of a putative insulator in this region could help to explain the challenges faced in this study and others to link SNPs associated with adiposity to altered <i>MC4R</i> expression.</p></div>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "adiposity", "melanocortin-4", "receptor", "replication", "characterization", "non-coding", "regions"], "article_id"=>1023403, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0096805.s001", "https://dx.doi.org/10.1371/journal.pone.0096805.s002", "https://dx.doi.org/10.1371/journal.pone.0096805.s003", "https://dx.doi.org/10.1371/journal.pone.0096805.s004", "https://dx.doi.org/10.1371/journal.pone.0096805.s005", "https://dx.doi.org/10.1371/journal.pone.0096805.s006", "https://dx.doi.org/10.1371/journal.pone.0096805.s007", "https://dx.doi.org/10.1371/journal.pone.0096805.s008", "https://dx.doi.org/10.1371/journal.pone.0096805.s009", "https://dx.doi.org/10.1371/journal.pone.0096805.s010"], "stats"=>{"downloads"=>29, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Genetic_Association_Study_of_Adiposity_and_Melanocortin_4_Receptor_MC4R_Common_Variants_Replication_and_Functional_Characterization_of_Non_Coding_Regions/1023403", "title"=>"Genetic Association Study of Adiposity and Melanocortin-4 Receptor (<i>MC4R</i>) Common Variants: Replication and Functional Characterization of Non-Coding Regions", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493566"], "description"=>"<p>Schematic depicting the genomic region (hg19 assembly) surrounding <i>MC4R</i> that contains rs11152221 (highlighted in red) and ENCODE-annotated insulators. Adapted from the UCSC Genome Browser, <a href=\"http://genome.ucsc.edu/\" target=\"_blank\">http://genome.ucsc.edu/</a><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096805#pone.0096805-Kent1\" target=\"_blank\">[51]</a>.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "transcriptional", "insulators"], "article_id"=>1023397, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ENCODE_based_transcriptional_insulators_near_MC4R_/1023397", "title"=>"ENCODE-based transcriptional insulators near <i>MC4R</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 02:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1493565"], "description"=>"<p>SNP genotypes from genome-wide Illumina array. Circles mark directly genotyped SNPs and triangles mark imputed SNPs. Gray points indicate association <i>P</i>-value >0.05. Red points indicate significant (<i>P</i>-value ≤0.05) associations with BMI. Anchor SNPs colored in blue. Purple circles mark SNP association with <i>MC4R</i> expression in HapMap YRI lymphoblastoid cell lines. In the panels showing trait association and eQTL <i>P</i>-values, the dashed line indicates cut-off value for Bonferroni-corrected <i>P</i>-value ≤0.05. LD heatmap indicates higher <i>r</i><sup>2</sup> measures with darker red colors. Nucleotide conservation between the human and mouse is indicated on the top panel of the figure and was obtained using the VISTA browser.</p>", "links"=>[], "tags"=>["genetics", "gene expression", "DNA transcription", "Human genetics", "Genetic association studies", "Gene function", "Genetics of disease", "nutrition", "physiology", "Physiological parameters", "Body weight", "obesity", "epidemiology", "Genetic epidemiology", "bmi", "genotyped", "imputed", "snps", "abc"], "article_id"=>1023396, "categories"=>["Biological Sciences"], "users"=>["Daniel S. Evans", "Melissa A. Calton", "Mee J. Kim", "Pui-Yan Kwok", "Iva Miljkovic", "Tamara Harris", "Annemarie Koster", "Yongmei Liu", "Gregory J. Tranah", "Nadav Ahituv", "Wen-Chi Hsueh", "Christian Vaisse"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0096805.g003", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_between_BMI_and_genotyped_and_imputed_SNPs_in_black_Health_ABC_participants_/1023396", "title"=>"Association between BMI and genotyped and imputed SNPs in black Health ABC participants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-05-12 02:51:46"}

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Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Developmental biology", "average_usage"=>[285]}, {"subject_area"=>"/Biology and life sciences/Genetics", "average_usage"=>[306, 482]}, {"subject_area"=>"/Medicine and health sciences/Physiology", "average_usage"=>[278]}]}
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