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Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants

Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts...

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Published in:International Journal of Obesity 2021, Vol.45 (1), p.155-169
Main Authors: Namjou, Bahram, Stanaway, Ian B., Lingren, Todd, Mentch, Frank D., Benoit, Barbara, Dikilitas, Ozan, Niu, Xinnan, Shang, Ning, Shoemaker, Ashley H., Carey, David J., Mirshahi, Tooraj, Singh, Rajbir, Nestor, Jordan G., Hakonarson, Hakon, Denny, Joshua C., Crosslin, David R., Jarvik, Gail P., Kullo, Iftikhar J., Williams, Marc S., Harley, John B.
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cited_by cdi_FETCH-LOGICAL-c4874-9f5e79e785c66d3bcbd59fbadfed83d2bd584c114ffe6bcf6e982eced45a9a453
cites cdi_FETCH-LOGICAL-c4874-9f5e79e785c66d3bcbd59fbadfed83d2bd584c114ffe6bcf6e982eced45a9a453
container_end_page 169
container_issue 1
container_start_page 155
container_title International Journal of Obesity
container_volume 45
creator Namjou, Bahram
Stanaway, Ian B.
Lingren, Todd
Mentch, Frank D.
Benoit, Barbara
Dikilitas, Ozan
Niu, Xinnan
Shang, Ning
Shoemaker, Ashley H.
Carey, David J.
Mirshahi, Tooraj
Singh, Rajbir
Nestor, Jordan G.
Hakonarson, Hakon
Denny, Joshua C.
Crosslin, David R.
Jarvik, Gail P.
Kullo, Iftikhar J.
Williams, Marc S.
Harley, John B.
description Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m 2 . In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 ( P  = 5.36 × 10 −25 , Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties ( P  = 6.23 × 10 −08 , Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.
doi_str_mv 10.1038/s41366-020-00675-4
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More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m 2 . In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 ( P  = 5.36 × 10 −25 , Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties ( P  = 6.23 × 10 −08 , Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.</description><identifier>ISSN: 0307-0565</identifier><identifier>ISSN: 1476-5497</identifier><identifier>EISSN: 1476-5497</identifier><identifier>DOI: 10.1038/s41366-020-00675-4</identifier><identifier>PMID: 32952152</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45 ; 45/23 ; 45/43 ; 631/208/135 ; 692/163/2743/393 ; Adult ; Aged ; Body Mass Index ; Body size ; Cell receptors ; Cohort Studies ; Diabetes mellitus (non-insulin dependent) ; Diabetic nephropathy ; Energy balance ; Epidemiology ; Female ; Food intake ; Genetic aspects ; Genetic research ; Genetic variation ; Genetic Variation - genetics ; Genome-Wide Association Study ; Genomes ; Genotyping ; Haplotypes ; Health aspects ; Health Promotion and Disease Prevention ; Homeostasis ; Humans ; Internal Medicine ; Male ; Medicine ; Medicine &amp; Public Health ; Melanocortin ; Melanocortin MC4 receptors ; Metabolic Diseases ; Middle Aged ; Nephropathy ; Obesity ; Obesity - epidemiology ; Obesity - genetics ; Public Health ; Receptor, Melanocortin, Type 4 - genetics ; Regression analysis ; Renal failure ; Risk factors</subject><ispartof>International Journal of Obesity, 2021, Vol.45 (1), p.155-169</ispartof><rights>The Author(s) 2020</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4874-9f5e79e785c66d3bcbd59fbadfed83d2bd584c114ffe6bcf6e982eced45a9a453</citedby><cites>FETCH-LOGICAL-c4874-9f5e79e785c66d3bcbd59fbadfed83d2bd584c114ffe6bcf6e982eced45a9a453</cites><orcidid>0000-0002-9906-8608 ; 0000-0003-1418-3103 ; 0000-0002-6524-3471 ; 0000-0002-0754-3820 ; 0000-0003-4452-7878</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32952152$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Namjou, Bahram</creatorcontrib><creatorcontrib>Stanaway, Ian B.</creatorcontrib><creatorcontrib>Lingren, Todd</creatorcontrib><creatorcontrib>Mentch, Frank D.</creatorcontrib><creatorcontrib>Benoit, Barbara</creatorcontrib><creatorcontrib>Dikilitas, Ozan</creatorcontrib><creatorcontrib>Niu, Xinnan</creatorcontrib><creatorcontrib>Shang, Ning</creatorcontrib><creatorcontrib>Shoemaker, Ashley H.</creatorcontrib><creatorcontrib>Carey, David J.</creatorcontrib><creatorcontrib>Mirshahi, Tooraj</creatorcontrib><creatorcontrib>Singh, Rajbir</creatorcontrib><creatorcontrib>Nestor, Jordan G.</creatorcontrib><creatorcontrib>Hakonarson, Hakon</creatorcontrib><creatorcontrib>Denny, Joshua C.</creatorcontrib><creatorcontrib>Crosslin, David R.</creatorcontrib><creatorcontrib>Jarvik, Gail P.</creatorcontrib><creatorcontrib>Kullo, Iftikhar J.</creatorcontrib><creatorcontrib>Williams, Marc S.</creatorcontrib><creatorcontrib>Harley, John B.</creatorcontrib><creatorcontrib>eMERGE Network</creatorcontrib><creatorcontrib>The eMERGE Network</creatorcontrib><title>Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants</title><title>International Journal of Obesity</title><addtitle>Int J Obes</addtitle><addtitle>Int J Obes (Lond)</addtitle><description>Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m 2 . In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 ( P  = 5.36 × 10 −25 , Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties ( P  = 6.23 × 10 −08 , Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.</description><subject>45</subject><subject>45/23</subject><subject>45/43</subject><subject>631/208/135</subject><subject>692/163/2743/393</subject><subject>Adult</subject><subject>Aged</subject><subject>Body Mass Index</subject><subject>Body size</subject><subject>Cell receptors</subject><subject>Cohort Studies</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetic nephropathy</subject><subject>Energy balance</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Food intake</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Genetic variation</subject><subject>Genetic Variation - genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genotyping</subject><subject>Haplotypes</subject><subject>Health aspects</subject><subject>Health Promotion and Disease Prevention</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine &amp; 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Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Psychology Database (ProQuest)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International Journal of Obesity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Namjou, Bahram</au><au>Stanaway, Ian B.</au><au>Lingren, Todd</au><au>Mentch, Frank D.</au><au>Benoit, Barbara</au><au>Dikilitas, Ozan</au><au>Niu, Xinnan</au><au>Shang, Ning</au><au>Shoemaker, Ashley H.</au><au>Carey, David J.</au><au>Mirshahi, Tooraj</au><au>Singh, Rajbir</au><au>Nestor, Jordan G.</au><au>Hakonarson, Hakon</au><au>Denny, Joshua C.</au><au>Crosslin, David R.</au><au>Jarvik, Gail P.</au><au>Kullo, Iftikhar J.</au><au>Williams, Marc S.</au><au>Harley, John B.</au><aucorp>eMERGE Network</aucorp><aucorp>The eMERGE Network</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants</atitle><jtitle>International Journal of Obesity</jtitle><stitle>Int J Obes</stitle><addtitle>Int J Obes (Lond)</addtitle><date>2021</date><risdate>2021</risdate><volume>45</volume><issue>1</issue><spage>155</spage><epage>169</epage><pages>155-169</pages><issn>0307-0565</issn><issn>1476-5497</issn><eissn>1476-5497</eissn><abstract>Background/Objectives Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus. Subjects/Methods The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping. Results Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m 2 . In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 ( P  = 5.36 × 10 −25 , Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties ( P  = 6.23 × 10 −08 , Beta = −0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI. Conclusions MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32952152</pmid><doi>10.1038/s41366-020-00675-4</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-9906-8608</orcidid><orcidid>https://orcid.org/0000-0003-1418-3103</orcidid><orcidid>https://orcid.org/0000-0002-6524-3471</orcidid><orcidid>https://orcid.org/0000-0002-0754-3820</orcidid><orcidid>https://orcid.org/0000-0003-4452-7878</orcidid><oa>free_for_read</oa></addata></record>
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1476-5497
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subjects 45
45/23
45/43
631/208/135
692/163/2743/393
Adult
Aged
Body Mass Index
Body size
Cell receptors
Cohort Studies
Diabetes mellitus (non-insulin dependent)
Diabetic nephropathy
Energy balance
Epidemiology
Female
Food intake
Genetic aspects
Genetic research
Genetic variation
Genetic Variation - genetics
Genome-Wide Association Study
Genomes
Genotyping
Haplotypes
Health aspects
Health Promotion and Disease Prevention
Homeostasis
Humans
Internal Medicine
Male
Medicine
Medicine & Public Health
Melanocortin
Melanocortin MC4 receptors
Metabolic Diseases
Middle Aged
Nephropathy
Obesity
Obesity - epidemiology
Obesity - genetics
Public Health
Receptor, Melanocortin, Type 4 - genetics
Regression analysis
Renal failure
Risk factors
title Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants
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