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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

ABSTRACT: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

SUBMITTER: Kilpelainen TO

PROVIDER: S-EPMC4740377 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Kilpeläinen Tuomas O TO Carli Jayne F Martin JF Skowronski Alicja A AA Sun Qi Q Kriebel Jennifer J Feitosa Mary F MF Hedman Åsa K ÅK Drong Alexander W AW Hayes James E JE Zhao Jinghua J Pers Tune H TH Schick Ursula U Grarup Niels N Kutalik Zoltán Z Trompet Stella S Mangino Massimo M Kristiansson Kati K Beekman Marian M Lyytikäinen Leo-Pekka LP Eriksson Joel J Henneman Peter P Lahti Jari J Tanaka Toshiko T Luan Jian'an J Del Greco M Fabiola F Pasko Dorota D Renström Frida F Willems Sara M SM Mahajan Anubha A Rose Lynda M LM Guo Xiuqing X Liu Yongmei Y Kleber Marcus E ME Pérusse Louis L Gaunt Tom T Ahluwalia Tarunveer S TS Ju Sung Yun Y Ramos Yolande F YF Amin Najaf N Amuzu Antoinette A Barroso Inês I Bellis Claire C Blangero John J Buckley Brendan M BM Böhringer Stefan S I Chen Yii-Der YD de Craen Anton J N AJ Crosslin David R DR Dale Caroline E CE Dastani Zari Z Day Felix R FR Deelen Joris J Delgado Graciela E GE Demirkan Ayse A Finucane Francis M FM Ford Ian I Garcia Melissa E ME Gieger Christian C Gustafsson Stefan S Hallmans Göran G Hankinson Susan E SE Havulinna Aki S AS Herder Christian C Hernandez Dena D Hicks Andrew A AA Hunter David J DJ Illig Thomas T Ingelsson Erik E Ioan-Facsinay Andreea A Jansson John-Olov JO Jenny Nancy S NS Jørgensen Marit E ME Jørgensen Torben T Karlsson Magnus M Koenig Wolfgang W Kraft Peter P Kwekkeboom Joanneke J Laatikainen Tiina T Ladwig Karl-Heinz KH LeDuc Charles A CA Lowe Gordon G Lu Yingchang Y Marques-Vidal Pedro P Meisinger Christa C Menni Cristina C Morris Andrew P AP Myers Richard H RH Männistö Satu S Nalls Mike A MA Paternoster Lavinia L Peters Annette A Pradhan Aruna D AD Rankinen Tuomo T Rasmussen-Torvik Laura J LJ Rathmann Wolfgang W Rice Treva K TK Brent Richards J J Ridker Paul M PM Sattar Naveed N Savage David B DB Söderberg Stefan S Timpson Nicholas J NJ Vandenput Liesbeth L van Heemst Diana D Uh Hae-Won HW Vohl Marie-Claude MC Walker Mark M Wichmann Heinz-Erich HE Widén Elisabeth E Wood Andrew R AR Yao Jie J Zeller Tanja T Zhang Yiying Y Meulenbelt Ingrid I Kloppenburg Margreet M Astrup Arne A Sørensen Thorkild I A TI Sarzynski Mark A MA Rao D C DC Jousilahti Pekka P Vartiainen Erkki E Hofman Albert A Rivadeneira Fernando F Uitterlinden André G AG Kajantie Eero E Osmond Clive C Palotie Aarno A Eriksson Johan G JG Heliövaara Markku M Knekt Paul B PB Koskinen Seppo S Jula Antti A Perola Markus M Huupponen Risto K RK Viikari Jorma S JS Kähönen Mika M Lehtimäki Terho T Raitakari Olli T OT Mellström Dan D Lorentzon Mattias M Casas Juan P JP Bandinelli Stefanie S März Winfried W Isaacs Aaron A van Dijk Ko W KW van Duijn Cornelia M CM Harris Tamara B TB Bouchard Claude C Allison Matthew A MA Chasman Daniel I DI Ohlsson Claes C Lind Lars L Scott Robert A RA Langenberg Claudia C Wareham Nicholas J NJ Ferrucci Luigi L Frayling Timothy M TM Pramstaller Peter P PP Borecki Ingrid B IB Waterworth Dawn M DM Bergmann Sven S Waeber Gérard G Vollenweider Peter P Vestergaard Henrik H Hansen Torben T Pedersen Oluf O Hu Frank B FB Eline Slagboom P P Grallert Harald H Spector Tim D TD Jukema J W JW Klein Robert J RJ Schadt Erik E EE Franks Paul W PW Lindgren Cecilia M CM Leibel Rudolph L RL Loos Ruth J F RJ

Nature communications 20160201

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify ...[more]

PMID: 26833098

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Project description:Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.

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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

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