B3 - Identification of Novel Genes Regulating Fat Distribution and Their Functional Relevance in Adipose Biology

Body fat distribution (FD) is one of the main predictors of obesity-associated complications. Waist to hip ratio (WHR), a surrogate measure of FD, shows heritability of up to 60%. Although numerous genetic variants associated with WHR have been reported in genome-wide association studies (GWAS), their exact role in FD remains unexplored. In preliminary studies, we demonstrated that the mRNA expression of multiple genes within loci associated with WHR differed between visceral and subcutaneous adipose tissue (VAT and SAT), and correlated with traits related to obesity, which was also linked to the variation in DNA methylation patterns. Moreover, the respective genetic variants were associated with transcript levels, indicating their functional relevance. Here, we will test the hypothesis that loci associated with FD carry genes regulating adipose tissue (AT) biology. To identify novel genes regulating FD, we will include more precise measurements of FD beyond WHR and perform a GWAS for variation in visceral and subcutaneous abdominal fat mass quantified by magnetic resonance imaging (MRI). To validate the predicted genetic targets of variants with a putative role in AT, we will conduct expression quantitative trait locus (eQTL) and methylation QTL analyses in human AT (paired VAT and SAT; N=1,000). Adipose biology affected by the revealed target genes will be investigated in vitro by using CRISPR/Cas9 genome editing followed by morphological and functional characterization of adipocytes, as well as in vivo by morpholino knockdown technology in the zebrafish. By integrating bioinformatics approaches with in vivo and in vitro strategies to predict and subsequently validate the functional role of identified genes and associated variants, the project should contribute to a better understanding of mechanisms underlying genetic mechanisms controlling variation in FD.

Figure 1. Our hypothesis is that fat distribution is controlled by a) genetic variants affecting gene expression in adipose tissue and/or the morphology and function of adipocytes and b) by alterations in DNA-methylation profiles.

Warrington NM, Beaumont RN, Horikoshi M, Day FR, Helgeland Ø, Laurin C, Bacelis J, Peng S, Hao K, Feenstra B, Wood AR, Mahajan A, Tyrrell J, Robertson
NR, Rayner NW, Qiao Z, Moen GH, Vaudel M, Marsit CJ, Chen J, Nodzenski M, Schnurr TM, Zafarmand MH, Bradfield JP, Grarup N, Kooijman MN, Li-Gao R, Geller F, Ahluwalia TS, Paternoster L, Rueedi R, Huikari V, Hottenga JJ, Lyytikäinen LP, Cavadino A, Metrustry S, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Vilor-Tejedor N, Joshi PK, Painter JN, Ntalla I, Myhre R, Pitkänen N, van Leeuwen EM, Joro R, Lagou V, Richmond RC, Espinosa A, Barton SJ, Inskip HM, Holloway JW, Santa-Marina L, Estivill X, Ang W, Marsh JA, Reichetzeder C, Marullo L, Hocher B, Lunetta KL, Murabito JM, Relton CL, Kogevinas M, Chatzi L, Allard C, Bouchard L, Hivert MF, Zhang G, Muglia LJ, Heikkinen J; EGG Consortium, Morgen CS, van Kampen AHC, van Schaik BDC, Mentch FD, Langenberg C, Luan J, Scott RA, Zhao JH, Hemani G, Ring SM, Bennett AJ, Gaulton KJ, Fernandez-Tajes J, van Zuydam NR, Medina-Gomez C, de Haan HG, Rosendaal FR, Kutalik Z, Marques-Vidal P, Das S, Willemsen G, Mbarek H, Müller-Nurasyid M, Standl M, Appel EVR, Fonvig CE, Trier C, van Beijsterveldt CEM, Murcia M, Bustamante M, Bonas-Guarch S, Hougaard DM, Mercader JM, Linneberg A, Schraut KE, Lind PA, Medland SE, Shields BM, Knight BA, Chai JF, Panoutsopoulou K, Bartels M, Sánchez F, Stokholm J, Torrents D, Vinding RK, Willems SM, Atalay M, Chawes BL, Kovacs P, Prokopenko I, Tuke MA, Yaghootkar H, Ruth KS, Jones SE, Loh PR, Murray A, Weedon MN, Tönjes A, Stumvoll M, Michaelsen KF, Eloranta AM, Lakka TA, van Duijn CM, Kiess W, Körner A, Niinikoski H, Pahkala K, Raitakari OT, Jacobsson B, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Montgomery GW, Campbell H, Wilson JF, Vrijkotte TGM, Vrijheid M, de Geus EJCN, Hayes MG, Kadarmideen HN, Holm JC, Beilin LJ, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén EE, Hattersley AT, Spector TD, Kähönen M, Viikari JS, Lehtimäki T, Boomsma DI, Sebert S, Vollenweider P, Sørensen TIA, Bisgaard H, Bønnelykke K, Murray JC, Melbye M, Nohr EA, Mook-Kanamori DO, Rivadeneira F, Hofman A, Felix JF, Jaddoe VWV, Hansen T, Pisinger C, Vaag AA, Pedersen O, Uitterlinden AG, Järvelin MR, Power C, Hyppönen E, Scholtens DM, Lowe WL Jr, Davey Smith G, Timpson NJ, Morris AP, Wareham NJ, Hakonarson H, Grant SFA, Frayling TM, Lawlor DA, Njølstad PR, Johansson S, Ong KK, McCarthy MI, Perry JRB, Evans DM, Freathy RM. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet. 2019 May;51(5):804-814.


Breitfeld J, Wiele N, Gutsmann B, Stumvoll M, Blüher M, Scholz M, Kovacs P, Tönjes A. Circulating Adipokine VASPIN Is Associated with Serum Lipid Profiles in Humans. Lipids. 2019 Mar 18.


Goldstein N, Haim Y, Mattar P, Hadadi-Bechor S, Maixner N, Kovacs PBlüher MRudich A. Leptin stimulates autophagy/lysosome-related degradation of long-lived proteins in adipocytes. Adipocyte. 2019 Jan 24.


Rohde K, Keller M, la Cour Poulsen L, Blüher M, Kovacs P, Böttcher Y. Genetics and epigenetics in obesity. Metabolism. 2018 Nov 3. pii: S0026-0495(18)30225-7.


Bartels MS, Scheffler L, Chakaroun R, Dietrich A, Blüher M, Stumvoll M, Tönjes A, Breitfeld J, Kovacs P. Increased circulating cell-free DNA in insulin resistance.Diabetes Metab. 2018 Jun 20.


Keller M, Klös M, Rohde K, Krüger J, Kurze T, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dreßler M, Stumvoll MBlüher M, Kovacs P, Böttcher Y. DNA methylation of SSPN is linked to adipose tissue distribution and glucose metabolism. FASEB J. 2018 Jun 22:fj201800528R.


Krüger J, Berger C, Weidle K, Schleinitz D, Tönjes A, Stumvoll MBlüher M, Kovacs P, Klöting N. Metabolic effects of genetic variation in the human REPIN1 gene. Circ Genom Precis Med. 2018 May;11(5):e001992.


Huhn S, Beyer F, Zhang R, Lampe L, Grothe J, Kratzsch J, Willenberg A, Breitfeld J, Kovacs PStumvoll M, Trampel R, Bazin PL, Villringer AWitte AV. Effects of resveratrol on glucose, memory and the hippocampus - a randomized controlled trial. Neuroimage. 2018 Mar 13;174:177-190.


Scheffler L, Crane A, Heyne H, Tönjes A, Schleinitz D, Ihling HC, Stumvoll M, Freire R, Fiorentino M, Fasano A, Kovacs P and Heiker JT. Widely Used commercial elisa. Does not Detect Precursor of haptoglobin2, but recognizes Properdin as a Potential second Member of the Zonulin Family. Front Endocrinol (Lausanne). 2018 Feb 5;9:22

Tönjes A, Scholz M, Krüger J, Krause K, Schleinitz D, Kirsten H, Gebhardt C, Marzi C, Grallert H, Ladenvall C, Heyne H, Laurila E, Kriebel J, Meisinger C, Rathmann W, Gieger C, Groop L, Prokopenko I, Isomaa B, Beutner F, Kratzsch J, Fischer-Rosinsky A, Pfeiffer A, Krohn K, Spranger J, Thiery J, Blüher M, Stumvoll M, Kovacs P. Genome-wide meta-analysis identifies novel determinants of circulating serum progranulin. Hum Mol Genet. 2018 Feb 1;27(3):546-558.

Gross A, Tönjes A, Scholz M. On the impact of relatedness on SNP association analysis. BMC Genet. 2017;18:104.

Rohde K, Klös M, Hopp L, Liu X, Keller M, Stumvoll M, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dreßler M, Kovacs P, Binder H, Blüher M, Böttcher Y. IRS1 DNA promoter methylation and expression in human adipose tissue are related to fat distribution and metabolic traits. Sci Rep. 2017;7:12369.

Rosendahl J, Kirsten H, Hegyi E, Kovacs P, Weiss FU, Laumen H, Lichtner P, Ruffert C, Chen JM, Masson E, Beer S, Zimmer C, Seltsam K, Algül H, Bühler F, Bruno MJ, Bugert P, Burkhardt R, Cavestro GM, Cichoz-Lach H, Farré A, Frank J, Gambaro G, Gimpfl S, Grallert H, Griesmann H, Grützmann R, Hellerbrand C, Hegyi P, Hollenbach M, Iordache S, Jurkowska G, Keim V, Kiefer F, Krug S, Landt O, Leo MD, Lerch MM, Lévy P, Löffler M, Löhr M, Ludwig M, Macek M, Malats N, Malecka-Panas E, Malerba G, Mann K, Mayerle J, Mohr S, Te Morsche RHM, Motyka M, Mueller S, Müller T, Nöthen MM, Pedrazzoli S, Pereira SP, Peters A, Pfützer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rösmann E, Saftoiu A, Schneider A, Schulz HU, Soranzo N, Soyka M, Simon P, Skipworth J, Stickel F, Strauch K, Stumvoll M, Testoni PA, Tönjes A, Werner L, Werner J, Wodarz N, Ziegler M, Masamune A, Mössner J, Férec C, Michl P, P H Drenth J, Witt H, Scholz M, Sahin-Tóth M; all members of the PanEuropean Working group on ACP. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. Gut. 2017; Epub ahead of print.

Weiner J, Rohde K, Krause K, Zieger K, Klöting N, Kralisch S, Kovacs P, Stumvoll M, Blüher M, Böttcher Y, Heiker JT. Brown adipose tissue (BAT) specific vaspin expression is increased after obesogenic diets and cold exposure and linked to acute changes in DNA-methylation. Mol Metab. 2017;6:482-93.

Keller M, Hopp L, Liu X, Wohland T, Rohde K, Cancello R, Klös M, Bacos K, Kern M, Eichelmann F, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dreßler M, Stumvoll M, Kovacs P, DiBlasio AM, Ling C, Binder H, Blüher M, Böttcher Y. Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity. Mol Metab. 2016;6:86-100

Ried JS, Jeff M J, Chu AY, Bragg-Gresham JL, van Dongen J, Huffman JE, Ahluwalia TS, Cadby G, Eklund N, Eriksson J, Esko T, Feitosa MF, Goel A, Gorski M, Hayward C, Heard-Costa NL, Jackson AU, Jokinen E, Kanoni S, Kristiansson K, Kutalik Z, Lahti J, Luan J, Mägi R, Mahajan A, Mangino M, Medina-Gomez C, Monda KL, Nolte IM, Pérusse L, Prokopenko I, Qi L, Rose LM, Salvi E, Smith MT, Snieder H, Stančáková A, Ju Sung Y, Tachmazidou I, Teumer A, Thorleifsson G, van der Harst P, Walker RW, Wang SR, Wild SH, Willems SM, Wong A, Zhang W, Albrecht E, Couto Alves A, Bakker SJ, Barlassina C, Bartz TM, Beilby J, Bellis C, Bergman RN, Bergmann S, Blangero J, Blüher M, Boerwinkle E, Bonnycastle LL, Bornstein SR, Bruinenberg M, Campbell H, Chen YI, Chiang CW, Chines PS, Collins FS, Cucca F, Cupples LA, D'Avila F, de Geus EJ, Dedoussis G, Dimitriou M, Döring A, Eriksson JG, Farmaki AE, Farrall M, Ferreira T, Fischer K, Forouhi NG, Friedrich N, Gjesing AP, Glorioso N, Graff M, Grallert H, Grarup N, Gräßler J, Grewal J, Hamsten A, Harder MN, Hartman CA, Hassinen M, Hastie N, Hattersley AT, Havulinna AS, Heliövaara M, Hillege H, Hofman A, Holmen O, Homuth G, Hottenga JJ, Hui J, Husemoen LL, Hysi PG, Isaacs A, Ittermann T, Jalilzadeh S, James AL, Jørgensen T, Jousilahti P, Jula A, Marie Justesen J, Justice AE, Kähönen M, Karaleftheri M, Tee Khaw K, Keinanen-Kiukaanniemi SM, Kinnunen L, Knekt PB, Koistinen HA, Kolcic I, Kooner IK, Koskinen S, Kovacs P, Kyriakou T, Laitinen T, Langenberg C, Lewin AM, Lichtner P, Lindgren CM, Lindström J, Linneberg A, Lorbeer R, Lorentzon M, Luben R, Lyssenko V, Männistö S, Manunta P, Leach IM, McArdle WL, Mcknight B, Mohlke KL, Mihailov E, Milani L, Mills R, Montasser ME, Morris AP, Müller G, Musk AW, Narisu N, Ong KK, Oostra BA, Osmond C, Palotie A, Pankow JS, Paternoster L, Penninx BW, Pichler I, Pilia MG, Polašek O, Pramstaller PP, Raitakari OT, Rankinen T, Rao DC, Rayner NW, Ribel-Madsen R, Rice TK, Richards M, Ridker PM, Rivadeneira F, Ryan KA, Sanna S, Sarzynski MA, Scholtens S, Scott RA, Sebert S, Southam L, Sparsø TH, Steinthorsdottir V, Stirrups K, Stolk RP, Strauch K, Stringham HM, Swertz MA, Swift AJ, Tönjes A, Tsafantakis E, van der Most PJ, Van Vliet-Ostaptchouk JV, Vandenput L, Vartiainen E, Venturini C, Verweij N, Viikari JS, Vitart V, Vohl MC, Vonk JM, Waeber G, Widén E, Willemsen G, Wilsgaard T, Winkler TW, Wright AF, Yerges-Armstrong LM, Hua Zhao J, Carola Zillikens M, Boomsma DI, Bouchard C, Chambers JC, Chasman DI, Cusi D, Gansevoort RT, Gieger C, Hansen T, Hicks AA, Hu F, Hveem K, Jarvelin MR, Kajantie E, Kooner JS, Kuh D, Kuusisto J, Laakso M, Lakka TA, Lehtimäki T, Metspalu A, Njølstad I, Ohlsson C, Oldehinkel AJ, Palmer LJ, Pedersen O, Perola M, Peters A, Psaty BM, Puolijoki H, Rauramaa R, Rudan I, Salomaa V, Schwarz PE, Shudiner AR, Smit JH, Sørensen TI, Spector TD, Stefansson K, Stumvoll M, Tremblay A, Tuomilehto J, Uitterlinden AG, Uusitupa M, Völker U, Vollenweider P, Wareham NJ, Watkins H, Wilson JF, Zeggini E, Abecasis GR, Boehnke M, Borecki IB, Deloukas P, van Duijn CM, Fox C, Groop LC, Heid IM, Hunter DJ, Kaplan RC, McCarthy MI, North KE, O'Connell JR, Schlessinger D, Thorsteinsdottir U, Strachan DP, Frayling T, Hirschhorn JN, Müller-Nurasyid M, Loos RJ. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat Commun. 2016;7:13357.

Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat Genet. 2016;48:1462-72.

Horikoshi M, Beaumont RN, Day FR, Warrington NM, Kooijman MN, Fernandez-Tajes J, Feenstra B, van Zuydam NR, Gaulton KJ, Grarup N, Bradfield JP, Strachan DP, Li-Gao R, Ahluwalia TS, Kreiner E, Rueedi R, Lyytikäinen LP, Cousminer DL, Wu Y, Thiering E, Wang CA, Have CT, Hottenga JJ, Vilor-Tejedor N, Joshi PK, Boh ET, Ntalla I, Pitkänen N, Mahajan A, van Leeuwen EM, Joro R, Lagou V, Nodzenski M, Diver LA, Zondervan KT, Bustamante M, Marques-Vidal P, Mercader JM, Bennett AJ, Rahmioglu N, Nyholt DR, Ma RC, Tam CH, Tam WH; CHARGE Consortium Hematology Working Group, Ganesh SK, van Rooij FJ, Jones SE, Loh PR, Ruth KS, Tuke MA, Tyrrell J, Wood AR, Yaghootkar H, Scholtens DM, Paternoster L, Prokopenko I, Kovacs P, Atalay M, Willems SM, Panoutsopoulou K, Wang X, Carstensen L, Geller F, Schraut KE, Murcia M, van Beijsterveldt CE, Willemsen G, Appel EV, Fonvig CE, Trier C, Tiesler CM, Standl M, Kutalik Z, Bonàs-Guarch S, Hougaard DM, Sánchez F, Torrents D, Waage J, Hollegaard MV, de Haan HG, Rosendaal FR, Medina-Gomez C, Ring SM, Hemani G, McMahon G, Robertson NR, Groves CJ, Langenberg C, Luan J, Scott RA, Zhao JH, Mentch FD, MacKenzie SM, Reynolds RM; Early Growth Genetics (EGG) Consortium, Lowe WL, Tönjes A, Stumvoll M, Lindi V, Lakka TA, van Duijn CM, Kiess W, Körner A, Sørensen TI, Niinikoski H, Pahkala K, Raitakari OT, Zeggini E, Dedoussis GV, Teo YY, Saw SM, Melbye M, Campbell H, Wilson JF, Vrijheid M, de Geus EJ, Boomsma DI, Kadarmideen HN, Holm JC, Hansen T, Sebert S, Hattersley AT, Beilin LJ, Newnham JP, Pennell CE, Heinrich J, Adair LS, Borja JB, Mohlke KL, Eriksson JG, Widén E, Kähönen M, Viikari JS, Lehtimäki T, Vollenweider P, Bønnelykke K, Bisgaard H, Mook-Kanamori DO, Hofman A, Rivadeneira F, Uitterlinden AG, Pisinger C, Pedersen O, Power C, Hyppönen E, Wareham NJ, Hakonarson H, Davies E, Walker BR, Jaddoe VW, Järvelin MR, Grant SF, Vaag AA, Lawlor DA, Frayling TM, Smith GD, Morris AP, Ong KK, Felix JF, Timpson NJ, Perry JR, Evans DM, McCarthy MI, Freathy RM. Genome-wide associations for birth weight and correlations with adult disease. Nature. 2016;538:248-52.

Guiu-Jurado E, Unthan M, Böhler N, Kern M, Landgraf K, Dietrich A, Schleinitz D, Ruschke K, Klöting N, Faßhauer M, Tönjes A, Stumvoll M, Körner A, Kovacs P, Blüher M. Bone morphogenetic protein 2 (BMP2) may contribute to partition of energy storage into visceral and subcutaneous fat depots. Obesity (Silver Spring). 2016;24:2092-100.

Winkler TW, Justice AE, Graff M, [...], Blüher M, [...], Kovacs P, [...], Tönjes A, [...], Stumvoll M, [...], Loos RJ. Correction. The influence of age and sex on genetic associations with adult body size and shape: A large-scale genome-wide interaction study. PLoS Genet. 2016;12:e1006166.

Lazaridis I, Nadel D, Rollefson G, Merrett DC, Rohland N, Mallick S, Fernandes D, Novac M, Gamarra B, Sirak K, Connell S, Stewardson K, Harney E, Fu Q, Gonzales-Fortes G, Jones ER, Roodenberg SA, Lengyel G, Bocquentin F, Gasparian B, Monge JM, Gregg M, Eshed V, Mizrahi AS, Meiklejohn C, Gerritsen F, Bejenaru L, Blüher M, Campbell A, Cavalleri G, Comas D, Froguel P, Gilbert E, Kerr SM, Kovacs P, Krause J, McGettigan D, Merrigan M, Merriwether DA, O'Reilly S, Richards MB, Semino O, Shamoon-Pour M, Stefanescu G, Stumvoll M, Tönjes A, Torroni A, Wilson JF, Yengo L, Hovhannisyan NA, Patterson N, Pinhasi R, Reich D. Genomic insights into the origin of farming in the ancient Near East. Nature. 2016;536:419-24.

Pfeiffer S, Krüger J, Maierhofer A, Böttcher Y, Klöting N, El Hajj N, Schleinitz D, Schön MR, Dietrich A, Fasshauer M, Lohmann T, Dreßler M, Stumvoll M, Haaf T, Blüher M, Kovacs P. Hypoxia-inducible factor 3A gene expression and methylation in adipose tissue is related to adipose tissue dysfunction. Sci Rep. 2016;6:27969.

Grellmann C, Neumann J, Bitzer S, Kovacs P, Tönjes A, Westlye LT, Anreassen OA, Stumvoll M, Villringer A, Horstmann A. Random projection for fast and efficient multivariate correlation analysis of high-dimensional data: A new approach. Front Genet. 2016;7:102.

Prasad RB, Lessmark A, Almgren P, Kovacs G, Hansson O, Oskolkov N, Vitai M, Ladenvall C, Kovacs P, Fadista J, Lachmann M, Zhou Y, Sonestedt E, Poon W, Wollheim CB, Orho-Melander M, Stumvoll M, Tuomi T, Pääbo S, Koranyi L, Groop L. Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes. Diabetologia. 2016;59:1702-13.

Voisin S, Almen MS, Zheleznyakova GY, Lundberg L, Zarei S, Castillo S, Eriksson FE, Nilsson EK, Blüher M, Böttcher Y, Kovacs P, Klovins J, Rask-Andersen M, Schiöth HB. Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers. Genome Med. 2015;7:103.

Winkler TW, Justice AE, Graff M, [...], Blüher M, [...], Kovacs P, [...], Stumvoll M, [...], Loos RJ. The influence of age and sex on genetic associations with adult body size and shape: A large-scale genome-wide interaction study. PLoS One. 2015;11:e1005378.

Burkhardt R, Kirsten H, Beutner F, Holdt LM, Gross A, Teren A, Tönjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, Scholz M. Integration of genome-wide SNP data and gene-expression profiles reveals six novel loci and regulatory mechanisms for amino acids and acylcarnitines in whole blood. PLoS Genet. 2015;11:e1005510.

Schunter JA, Löffler D, Wiesner T, Kovacs P, Badenhoop K, Aust G, Tönjes A, Müller P, Baber R, Simon JC, Führer D, Pfäffle RW, Thiery J, Stumvoll M, Kiess W, Kratzsch J, Körner A. A novel FoxD3 variant is associated with vitiligo and elevated thyroid auto-antibodies. J Clin Endocrinol Metab. 2015;100:E1335-42.

Popkova Y, Meusel A, Breitfeld J, Schleinitz D, Hirrlinger J, Dannenberger D, Kovacs P, Schiller J. Nutrition-dependent changes of mouse adipose tissue compositions monitored by NMR, MS, and chromatographic methods. Anal Bioanal Chem. 2015;407:5113-23.

Rohde K, Federbusch M, Horstmann A, Keller M, Villringer A, Stumvoll M, Tönjes A, Kovacs P, Böttcher Y. Genetic variants in AKR1B10 associate with human eating behavior. BMC Genet. 2015;16:31.

Knigge A, Klöting N, Schön MR, Dietrich A, Fasshauer M, Gärtner D, Lohmann T, Dreßler M, Stumvoll M, Kovacs P, Blüher M. ADCY5 gene expression in adipose tissue is related to obesity in men and mice. PLoS One. 2015;10:e0120742.

Rohde K, Keller M, Horstmann A, Liu X, Eichelmann F, Stumvoll M, Villringer A, Kovacs P, Tönjes A, Böttcher Y. Role of genetic variants in ADIPOQ in human eating behavior. Genes Nutr. 2015;10:449.

Shungin D, Winkler TW, Croteau-Chonka DC, Ferreira T, Locke AE, Mägi R, Strawbridge RJ, Pers TH, Fischer K, [….], Kovacs P, [….], Zillikens MC, McCarthy MI, Speliotes EK, North KE, Fox CS, Barroso I, Franks PW, Ingelsson E, Heid IM, Loos RJ, Cupples LA, Morris AP, Lindgren CM, Mohlke KL. New genetic loci link adipose and insulin biology to body fat distribution. Nature. 2015;518:187-96.

Kern M, Kosacka J, Brückner J, Hesselbarth N, Heiker J, Flehmig G, Klöting I, Kovacs P, Matz-Soja M, Gebhardt R, Krohn K, Sales S, Shevchenko A, Abshagen K, Stumvoll M, Blüher M, Klöting N. Liver-restricted Repin1 Deficiency Improves Whole Body Insulin Sensitivity, Alters Lipid Metabolism and Causes Secondary Changes in Adipose Tissue in Mice. Diabetes. 2014:63:3295-309.

Keller M, Kralisch S, Rohde K, Schleinitz D, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dreßler M, Tönjes A, Stumvoll M, Kovacs P, Faßhauer M, Blüher M, Böttcher Y. Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis. Diabetologia. 2014;57:2374-83.

Derikx MH, Kovacs P, Scholz M, Masson E, Chen JM, Ruffert C, Lichtner P, Te Morsche RH, Cavestro GM, Algül H, Berg T, Bödeker H, Blüher M, Bruno MJ, Buch S, Bugert P, Cichoz-Lach H, Dabrowski A, Farré A, Frank J, Gasiorowska A, Geisz A, Goni E, Grothaus J, Grützmann R, Haas S, Hampe J, Hellerbrand C, Hegyi P, Huster D, Ioana M, Iordache S, Jurkowska G, Keim V, Landt O, Di Leo M, Lerch MM, Lévy P, Löhr MJ, Macek M, Malats N, Malecka-Panas E, Mariani A, Martorana D, Mayerle J, Mora J, Mössner J, Müller S, Ockenga J, Paderova J, Pedrazzoli S, Pereira SP, Pfützer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rohde K, Sack S, Saftoiu A, Schneider A, Schulz HU, Soyka M, Simon P, Skipworth J, Stickel F, Stumvoll M, Testonin PA, Tönjes A, Treiber M, Weiss FU, Werner J, Wodarz N, Férec C, Drenth JP, Witt H, Rosendahl. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study. Gut. 2014;64:1426-33.

Tönjes A, Scholz M, Breitfeld J, Marzi C, Grallert H, Gross A, Ladenvall C, Schleinitz D, Krause K, Kirsten H, Laurila E, Kriebel J, Thorand B, Rathmann W, Groop L, Prokopenko I, Isomaa B, Beutner F, Kratzsch J, Thiery J, Fasshauer M, Klöting N, Gieger C, Blüher M, Stumvoll M, Kovacs P. Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin. PLoS Genet. 2014;10:e1004854.

Rohde K, Keller M, Klös M, Schleinitz D, Dietrich A, Schön MR, Gärtner D, Lohmann T, Dreßler M, Stumvoll M, Kovacs P, Blüher M, Böttcher Y. Adipose tissue depot specific promotor methylation of TMEM18. J Mol Med. 2014;92:881-8.

Schleinitz D, Böttcher Y, Blüher M, Kovacs P. The genetics of fat distribution. Diabetologia. 2014;57:1276-86.

Schleinitz D, Klöting N, Lindgren CM, Breitfeld J, Dietrich A, Schön MR, Lohmann T, Dreßler M, Stumvoll M, McCarthy MI, Blüher M, Kovacs P. Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio. Int J Obes (Lond). 2014;38:120-5.

Keller M, Liu X, Wohland T, Rohde K, Gast MT, Stumvoll M, Kovacs P, Tönjes A, Böttcher Y. TAS2R38 and its influence on smoking behavior and glucose homeostasis in the German Sorbs. PLoS One. 2013;8:e80512.

Hoffmeister A, Tuennemann J, Sommerer I, Mössner J, Rittger A, Schleinitz D, Kratzsch J, Rosendahl J, Klöting N, Stahl T, Rossner S, Paroni F, Maedler K, Kovacs P, Blüher M. Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression. Obesity (Silver Spring). 2013;21:E626-33.

Keller M, Schleinitz D, Förster J, Tönjes A, Böttcher Y, Fischer-Rosinsky A, Breitfeld J, Weidle K, Rayner NW, Burkhardt R, Enigk B, Müller I, Halbritter J, Koriath M, Pfeiffer A, Krohn K, Groop L, Spranger J, Stumvoll M, Kovacs P. THOC5 : a novel gene involved in HDL-cholesterol metabolism. J Lipid Res. 2013;54:3170-6.

Heiker JT, Kern M, Kosacka J, Flehmig G, Stumvoll M, Shang E, Lohmann T, Dreßler M, Kovacs P, Blüher M, Klöting N. Nicotinamide nucleotide transhydrogenase mRNA expression is related to human obesity. Obesity (Silver Spring). 2013;21:529-34.

Kovacs P, Miehle K, Sandner B, Stumvoll M, Blüher M. Insulin administration acutely decreases vaspin serum concentrations in humans. Obes Facts. 2013;6:86-8.

Mai M, Tönjes A, Kovacs P, Stumvoll M, Fiedler GM, Leichtle AB. Serum levels of acylcarnitines are altered in prediabetic conditions. PLoS ONE. 2013;8:e82459.

Gast MT, Tönjes A, Keller M, Horstmann A, Steinle N, Scholz M, Müller I, Villringer A, Stumvoll M, Kovacs P, Böttcher Y. The role of rs2237781 within GRM8 in eating behavior. Brain Behav. 2013;5:495-502.

Horstmann A, Kovacs P, Kabisch S, Boettcher Y, Schloegl H, Toenjes A, Stumvoll M, Pleger B, Villringer A. Common genetic variation near MC4R has a sex-specific impact on human brain structure and brain behavior. PLoS One. 2013;8:e74362.

Schleinitz D, Klöting N, Böttcher Y, Wolf S, Dietrich K, Tönjes A, Breitfeld J, Enigk B, Halbritter J, Körner A, Schön MR, Jenkner J, Tseng Y-H, Stumvoll M, Blüher M, Kovacs P. Human Bone Morphogenetic Protein Receptor 2 (BMPR2) is Involved in the Pathophysiology of Obesity. PLoS One. 2011;6:e16155.

Klöting N*, Kovacs P*, Kern M, Heiker JT, Schön MR, Stumvoll M, Beck-Sickinger AG, Blüher M. Central vaspin administration acutely reduces food intake with sustained blood glucose lowering effects. Diabetologia. 2011;54:1819-23.

Schleinitz D, Klöting N, Körner A, Berndt J, Reichenbächer M, Tönjes A, Ruschke K, Böttcher Y, Dietrich K, Enigk B, Filz M, Schön MR, Jenkner J, Kiess W, Stumvoll M, Blüher M, Kovacs P. Effect of genetic variation in the human fatty acid synthase gene (FASN) on obesity and fat depot-specific mRNA expression. Obesity. 2010;18:1218-25.

Heid IM, Jackson AU, Randall JC, Winkler TW, [...], Kovacs P, Kroemer HK, [...], McCarthy MI, Fox CS, Mohlke KL, Lindgren CM. Meta-analysis identifies 13 novel loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010;42:949-60.

Böttcher Y*, Unbehauen H*, Klöting N, Ruschke K, Körner A, Schleinitz D, Tönjes A, Enigk B, Dietrich K, Koriath M, Scholz GH, Tseng Y, Schön MR, Kiess W, Stumvoll M, Blüher M, Kovacs P. Adipose Tissue Expression and Genetic Variants of the Bone Morphogenetic Protein Receptor 1A Gene (BMPR1A) are Associated with Human Obesity. Diabetes. 2009;58:2119-28.

Klöting N*, Schleinitz D*, Ruschke K, Berndt J, Fasshauer M, Tönjes A, Schön MR, Kovacs P, Stumvoll M, Blüher M. Inverse relationship between obesity and FTO gene expression in visceral adipose tissue in humans. Diabetologia. 2008;51:641-7.

Kovacs P*, Geyer M*, Berndt J, Klöting N, Graham TE, Böttcher Y, Enigk B, Tönjes A, Schleinitz D, Schön MR, Kahn BB, Blüher M, Stumvoll M. Effects of Genetic Variation in the Human Retinol Binding Protein-4 Gene (RBP4) on Insulin Resistance and Fat Depot Specific mRNA Expression. Diabetes. 2007;56:3095-100.

Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll M, Blüher M. Vaspin gene expression in human adipose tissue: Association with obesity and type 2 diabetes. Biochem Biophys Res Commun. 2006;339:430-6.
(* contributed equally)

PROJECT TEAM

Sun Chang, Phd student

sun.chang@medizin.uni-leipzig.de

Anna Seidel, Phd student

Lucas Scheffler, Phd student