TY - JOUR
T1 - Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants
AU - The eMERGE Network
AU - Namjou, Bahram
AU - Stanaway, Ian B.
AU - Lingren, Todd
AU - Mentch, Frank D.
AU - Benoit, Barbara
AU - Dikilitas, Ozan
AU - Niu, Xinnan
AU - Shang, Ning
AU - Shoemaker, Ashley H.
AU - Carey, David J.
AU - Mirshahi, Tooraj
AU - Singh, Rajbir
AU - Nestor, Jordan G.
AU - Hakonarson, Hakon
AU - Denny, Joshua C.
AU - Crosslin, David R.
AU - Jarvik, Gail P.
AU - Kullo, Iftikhar J.
AU - Williams, Marc S.
AU - Harley, John B.
N1 - Funding Information:
Acknowledgements In eMERGE network (Phase 3 ascertainment), this phase of the eMERGE Network was initiated and funded by the NHGRI through the following grants: U01HG008666 (Cincinnati Children’s Hospital Medical Center); U01HG008657 (Kaiser Washington/University of Washington); U01HG008685 (Brigham and Women’ s Hospital); U01H00G8672 (Vanderbilt University Medical Center); U01HG006379 (Mayo Clinic); U01HG008679 (Geisinger Clinic); U01HG008680 (Columbia University Health Sciences); U01HG008684 (Children’s Hospital of Philadelphia); U01HG008673 (Northwestern University); U01HG008701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG00676 (Partners Health-care/Broad Institute); and U01HG008664 (Baylor College of Medicine). In eMERGE network (Phase 1 and 2 ascertainment), the eMERGE Network was initiated and funded by NHGRI through the following grants: U01HG006828 (Cincinnati Children s Hospital Medical Center/Boston Children’s Hospital); U01HG006830 (Children’s Hospital of Philadelphia); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006382 (Geisinger Clinic); U01HG006375 (Group Health (now Kaiser Permanente Washington Health Research Institute)/University of Washington; U01HG006379 (Mayo Clinic); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG006388 (Northwestern University); U01HG006378 (Vanderbilt University Medical Center);and U01HG006385 (Vanderbilt University Medical Center serving as the Coordinating Center) with U01HG004438 (CIDR) and U01HG004424 (the Broad Institute) serving as Genotyping Centers. This project was also supported by U01AI130830, P30AR070549, and R01AI024717 and the US Department of Veterans Affairs (I01BX001834).
Publisher Copyright:
© 2020, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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/m2. 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.
AB - 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/m2. 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.
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U2 - 10.1038/s41366-020-00675-4
DO - 10.1038/s41366-020-00675-4
M3 - Article
C2 - 32952152
AN - SCOPUS:85091165640
SN - 0307-0565
VL - 45
SP - 155
EP - 169
JO - International Journal of Obesity
JF - International Journal of Obesity
IS - 1
ER -