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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genet., 50 (1). S. 26 - 45. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
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Lin, Li-AnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, XuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lind, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindstrom, JaanaUNSPECIFIEDorcid.org/0000-0001-9255-020XUNSPECIFIED
Linneberg, AllanUNSPECIFIEDorcid.org/0000-0002-0994-0184UNSPECIFIED
Liu, Ching-TiUNSPECIFIEDorcid.org/0000-0002-0703-0742UNSPECIFIED
Liu, Dajiang J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, YongmeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lo, Ken S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lophatananon, ArtitayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lotery, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loukola, AnuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luan, Jian'anUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubitz, Steven A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lyytikainen, Leo-PekkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannisto, SatuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marenne, GaelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mazul, Angela L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McCarthy, Mark I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKean-Cowdin, RobertaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medland, Sarah E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meidtner, KarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milani, LiliUNSPECIFIEDorcid.org/0000-0002-5323-3102UNSPECIFIED
Mistry, VanishaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitchell, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohlke, Karen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moilanen, LeenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moitry, MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montgomery, Grant W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mook-Kanamori, Dennis O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, CarmelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mori, Trevor A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, Andrew D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morris, Andrew P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller-Nurasyid, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munroe, Patricia B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nalls, Mike A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Narisu, NarisuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nelson, Christopher P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neville, MattUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Sune F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikus, KjellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Njolstad, Pal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordestgaard, Borge G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nyholt, Dale R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Connel, Jeffrey R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Donoghue, Michelle L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loohuis, Loes M. OldeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ophoff, Roel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Owen, Katharine R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Packard, Chris J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Padmanabhan, SandoshUNSPECIFIEDorcid.org/0000-0003-3869-5808UNSPECIFIED
Palmer, Colin N. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palmer, Nicholette D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasterkamp, GerardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, Aniruddh P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pattie, AlisonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, OlufUNSPECIFIEDorcid.org/0000-0002-3321-3972UNSPECIFIED
Peissig, Peggy L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peloso, Gina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pennell, Craig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perola, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perry, James A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perry, John R. B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pers, Tune H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Person, Thomas N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, AnnetteUNSPECIFIEDorcid.org/0000-0001-6645-0985UNSPECIFIED
Petersen, Eva R. B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peyser, Patricia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pirie, AilithUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Polasek, OzrenUNSPECIFIEDorcid.org/0000-0002-5765-1862UNSPECIFIED
Polderman, Tinca J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puolijoki, HannuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raitakari, Olli T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rasheed, AsifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauramaa, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reilly, Dermot F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renstrom, FridaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rheinberger, MyriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ridker, Paul M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rioux, John D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivas, Manuel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roberts, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robertson, Neil R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robino, AntoniettaUNSPECIFIEDorcid.org/0000-0003-2152-2353UNSPECIFIED
Rolandsson, OlovUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudan, IgorUNSPECIFIEDorcid.org/0000-0001-6993-6884UNSPECIFIED
Ruth, Katherine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saleheen, DanishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salomaa, VeikkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samani, Nilesh J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sapkota, YadavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sattar, NaveedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoen, Robert E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schreiner, Pamela J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulze, Matthias B.UNSPECIFIEDorcid.org/0000-0002-0830-5277UNSPECIFIED
Scott, Robert A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segura-Lepe, Marcelo P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shah, Svati H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sheu, Wayne H. -H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sim, XuelingUNSPECIFIEDorcid.org/0000-0002-1233-7642UNSPECIFIED
Slater, Andrew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Small, Kerrin S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, Albert V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southam, LorraineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spector, Timothy D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speliotes, Elizabeth K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Starr, John M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stefansson, KariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinthorsdottir, ValgerdurUNSPECIFIEDorcid.org/0000-0003-1846-6274UNSPECIFIED
Stirrups, Kathleen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strauch, KonstantinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stringham, Heather M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stumvoll, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, LiangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Surendran, PraveenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swift, Amy J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tada, HayatoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tansey, Katherine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tardif, Jean-ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Kent D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teumer, AlexanderUNSPECIFIEDorcid.org/0000-0002-8309-094XUNSPECIFIED
Thompson, Deborah J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorleifsson, GudmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorsteinsdottir, UnnurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thuesen, Betina H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toenjes, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tromp, GerardUNSPECIFIEDorcid.org/0000-0002-7761-0806UNSPECIFIED
Trompet, StellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsafantakis, EmmanouilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuomilehto, JaakkoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tybjaerg-Hansen, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tyrer, Jonathan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uher, RudolfUNSPECIFIEDorcid.org/0000-0002-2998-0546UNSPECIFIED
Uitterlinden, Andre G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uusitupa, MattiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laan, Sander W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leeuwen, NienkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Setten, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanhala, MaunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varbo, AnetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varga, Tibor V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varma, RohitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edwards, Digna R. VelezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vermeulen, Sita H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veronesi, GiovanniUNSPECIFIEDorcid.org/0000-0002-4119-6615UNSPECIFIED
Vestergaard, HenrikUNSPECIFIEDorcid.org/0000-0003-3090-269XUNSPECIFIED
Vitart, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogt, Thomas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Voelker, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vuckovic, DraganaUNSPECIFIEDorcid.org/0000-0001-9343-6142UNSPECIFIED
Wagenknecht, Lynne E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wallentin, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, FeijieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, Carol A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, ShuaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, YiqinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ware, Erin B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wareham, Nicholas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warren, Helen R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waterworth, Dawn M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wessel, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, Harvey D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willer, Cristen J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilson, James G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witte, Daniel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wood, Andrew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, YingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yaghootkar, HaniehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yao, JieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yao, PangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yerges-Armstrong, Laura M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeggini, EleftheriaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhan, XiaoweiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, WeihuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, Jing HuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, WeiUNSPECIFIEDorcid.org/0000-0002-8301-9297UNSPECIFIED
Zhou, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zondervan, Krina T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rotter, Jerome I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pospisilik, John A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rivadeneira, FernandoUNSPECIFIEDorcid.org/0000-0001-9435-9441UNSPECIFIED
Borecki, Ingrid B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deloukas, PanosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frayling, Timothy M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lettre, GuillaumeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
North, Kari E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindgren, Cecilia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hirschhorn, Joel N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loos, Ruth J. F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-200825
DOI: 10.1038/s41588-017-0011-x
Journal or Publication Title: Nature Genet.
Volume: 50
Number: 1
Page Range: S. 26 - 45
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; MELANOCORTIN-4 RECEPTOR GENE; DONEPEZIL 23 MG; FRAMESHIFT MUTATION; GLUCOSE-HOMEOSTASIS; HYPOTHALAMIC AMPK; CODING VARIANTS; BLOOD-PRESSURE; RARE; LOCIMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20082

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