@article {8570, title = {A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 11 23}, pages = {13357}, abstract = {

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99\% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

}, keywords = {Anthropometry, Body Size, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Principal Component Analysis}, issn = {2041-1723}, doi = {10.1038/ncomms13357}, author = {Ried, Janina S and Jeff M, Janina and Chu, Audrey Y and Bragg-Gresham, Jennifer L and van Dongen, Jenny and Huffman, Jennifer E and Ahluwalia, Tarunveer S and Cadby, Gemma and Eklund, Niina and Eriksson, Joel and Esko, T{\~o}nu and Feitosa, Mary F and Goel, Anuj and Gorski, Mathias and Hayward, Caroline and Heard-Costa, Nancy L and Jackson, Anne U and Jokinen, Eero and Kanoni, Stavroula and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lahti, Jari and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mahajan, Anubha and Mangino, Massimo and Medina-G{\'o}mez, Carolina and Monda, Keri L and Nolte, Ilja M and Perusse, Louis and Prokopenko, Inga and Qi, Lu and Rose, Lynda M and Salvi, Erika and Smith, Megan T and Snieder, Harold and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tachmazidou, Ioanna and Teumer, Alexander and Thorleifsson, Gudmar and van der Harst, Pim and Walker, Ryan W and Wang, Sophie R and Wild, Sarah H and Willems, Sara M and Wong, Andrew and Zhang, Weihua and Albrecht, Eva and Couto Alves, Alexessander and Bakker, Stephan J L and Barlassina, Cristina and Bartz, Traci M and Beilby, John and Bellis, Claire and Bergman, Richard N and Bergmann, Sven and Blangero, John and Bl{\"u}her, Matthias and Boerwinkle, Eric and Bonnycastle, Lori L and Bornstein, Stefan R and Bruinenberg, Marcel and Campbell, Harry and Chen, Yii-Der Ida and Chiang, Charleston W K and Chines, Peter S and Collins, Francis S and Cucca, Fracensco and Cupples, L Adrienne and D{\textquoteright}Avila, Francesca and de Geus, Eco J C and Dedoussis, George and Dimitriou, Maria and D{\"o}ring, Angela and Eriksson, Johan G and Farmaki, Aliki-Eleni and Farrall, Martin and Ferreira, Teresa and Fischer, Krista and Forouhi, Nita G and Friedrich, Nele and Gjesing, Anette Prior and Glorioso, Nicola and Graff, Mariaelisa and Grallert, Harald and Grarup, Niels and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Hamsten, Anders and Harder, Marie Neergaard and Hartman, Catharina A and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew Tym and Havulinna, Aki S and Heli{\"o}vaara, Markku and Hillege, Hans and Hofman, Albert and Holmen, Oddgeir and Homuth, Georg and Hottenga, Jouke-Jan and Hui, Jennie and Husemoen, Lise Lotte and Hysi, Pirro G and Isaacs, Aaron and Ittermann, Till and Jalilzadeh, Shapour and James, Alan L and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Marie Justesen, Johanne and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Karaleftheri, Maria and Tee Khaw, Kay and Keinanen-Kiukaanniemi, Sirkka M and Kinnunen, Leena and Knekt, Paul B and Koistinen, Heikki A and Kolcic, Ivana and Kooner, Ishminder K and Koskinen, Seppo and Kovacs, Peter and Kyriakou, Theodosios and Laitinen, Tomi and Langenberg, Claudia and Lewin, Alexandra M and Lichtner, Peter and Lindgren, Cecilia M and Lindstr{\"o}m, Jaana and Linneberg, Allan and Lorbeer, Roberto and Lorentzon, Mattias and Luben, Robert and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Manunta, Paolo and Leach, Irene Mateo and McArdle, Wendy L and McKnight, Barbara and Mohlke, Karen L and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Montasser, May E and Morris, Andrew P and M{\"u}ller, Gabriele and Musk, Arthur W and Narisu, Narisu and Ong, Ken K and Oostra, Ben A and Osmond, Clive and Palotie, Aarno and Pankow, James S and Paternoster, Lavinia and Penninx, Brenda W and Pichler, Irene and Pilia, Maria G and Polasek, Ozren and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rayner, Nigel W and Ribel-Madsen, Rasmus and Rice, Treva K and Richards, Marcus and Ridker, Paul M and Rivadeneira, Fernando and Ryan, Kathy A and Sanna, Serena and Sarzynski, Mark A and Scholtens, Salome and Scott, Robert A and Sebert, Sylvain and Southam, Lorraine and Spars{\o}, Thomas Hempel and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stolk, Ronald P and Strauch, Konstantin and Stringham, Heather M and Swertz, Morris A and Swift, Amy J and T{\"o}njes, Anke and Tsafantakis, Emmanouil and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Vartiainen, Erkki and Venturini, Cristina and Verweij, Niek and Viikari, Jorma S and Vitart, Veronique and Vohl, Marie-Claude and Vonk, Judith M and Waeber, G{\'e}rard and Widen, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Winkler, Thomas W and Wright, Alan F and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Zillikens, M Carola and Boomsma, Dorret I and Bouchard, Claude and Chambers, John C and Chasman, Daniel I and Cusi, Daniele and Gansevoort, Ron T and Gieger, Christian and Hansen, Torben and Hicks, Andrew A and Hu, Frank and Hveem, Kristian and Jarvelin, Marjo-Riitta and Kajantie, Eero and Kooner, Jaspal S and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Metspalu, Andres and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Palmer, Lyle J and Pedersen, Oluf and Perola, Markus and Peters, Annette and Psaty, Bruce M and Puolijoki, Hannu and Rauramaa, Rainer and Rudan, Igor and Salomaa, Veikko and Schwarz, Peter E H and Shudiner, Alan R and Smit, Jan H and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Tremblay, Angelo and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and V{\"o}lker, Uwe and Vollenweider, Peter and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Zeggini, Eleftheria and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and van Duijn, Cornelia M and Fox, Caroline and Groop, Leif C and Heid, Iris M and Hunter, David J and Kaplan, Robert C and McCarthy, Mark I and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Thorsteinsdottir, Unnur and Strachan, David P and Frayling, Timothy and Hirschhorn, Joel N and M{\"u}ller-Nurasyid, Martina and Loos, Ruth J F} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7668, title = {Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {559-571}, abstract = {

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 {\texttimes} 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteright}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0084-1}, author = {Mahajan, Anubha and Wessel, Jennifer and Willems, Sara M and Zhao, Wei and Robertson, Neil R and Chu, Audrey Y and Gan, Wei and Kitajima, Hidetoshi and Taliun, Daniel and Rayner, N William and Guo, Xiuqing and Lu, Yingchang and Li, Man and Jensen, Richard A and Hu, Yao and Huo, Shaofeng and Lohman, Kurt K and Zhang, Weihua and Cook, James P and Prins, Bram Peter and Flannick, Jason and Grarup, Niels and Trubetskoy, Vassily Vladimirovich and Kravic, Jasmina and Kim, Young Jin and Rybin, Denis V and Yaghootkar, Hanieh and M{\"u}ller-Nurasyid, Martina and Meidtner, Karina and Li-Gao, Ruifang and Varga, Tibor V and Marten, Jonathan and Li, Jin and Smith, Albert Vernon and An, Ping and Ligthart, Symen and Gustafsson, Stefan and Malerba, Giovanni and Demirkan, Ayse and Tajes, Juan Fernandez and Steinthorsdottir, Valgerdur and Wuttke, Matthias and Lecoeur, C{\'e}cile and Preuss, Michael and Bielak, Lawrence F and Graff, Marielisa and Highland, Heather M and Justice, Anne E and Liu, Dajiang J and Marouli, Eirini and Peloso, Gina Marie and Warren, Helen R and Afaq, Saima and Afzal, Shoaib and Ahlqvist, Emma and Almgren, Peter and Amin, Najaf and Bang, Lia B and Bertoni, Alain G and Bombieri, Cristina and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Burtt, Noel P and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Cho, Yoon Shin and Christensen, Cramer and Eastwood, Sophie V and Eckardt, Kai-Uwe and Fischer, Krista and Gambaro, Giovanni and Giedraitis, Vilmantas and Grove, Megan L and de Haan, Hugoline G and Hackinger, Sophie and Hai, Yang and Han, Sohee and Tybj{\ae}rg-Hansen, Anne and Hivert, Marie-France and Isomaa, Bo and J{\"a}ger, Susanne and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kim, Bong-Jo and Kim, Sung Soo and Koistinen, Heikki A and Kovacs, Peter and Kriebel, Jennifer and Kronenberg, Florian and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Jung-Jin and Lehne, Benjamin and Li, Huaixing and Lin, Keng-Hung and Linneberg, Allan and Liu, Ching-Ti and Liu, Jun and Loh, Marie and M{\"a}gi, Reedik and Mamakou, Vasiliki and McKean-Cowdin, Roberta and Nadkarni, Girish and Neville, Matt and Nielsen, Sune F and Ntalla, Ioanna and Peyser, Patricia A and Rathmann, Wolfgang and Rice, Kenneth and Rich, Stephen S and Rode, Line and Rolandsson, Olov and Sch{\"o}nherr, Sebastian and Selvin, Elizabeth and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Surendran, Praveen and Taylor, Kent D and Teslovich, Tanya M and Thorand, Barbara and Thorleifsson, Gudmar and Tin, Adrienne and T{\"o}njes, Anke and Varbo, Anette and Witte, Daniel R and Wood, Andrew R and Yajnik, Pranav and Yao, Jie and Yengo, Loic and Young, Robin and Amouyel, Philippe and Boeing, Heiner and Boerwinkle, Eric and Bottinger, Erwin P and Chowdhury, Rajiv and Collins, Francis S and Dedoussis, George and Dehghan, Abbas and Deloukas, Panos and Ferrario, Marco M and Ferrieres, Jean and Florez, Jose C and Frossard, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Heckbert, Susan R and Howson, Joanna M M and Ingelsson, Martin and Kathiresan, Sekar and Kee, Frank and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lindgren, Cecilia M and M{\"a}nnist{\"o}, Satu and Meitinger, Thomas and Melander, Olle and Mohlke, Karen L and Moitry, Marie and Morris, Andrew D and Murray, Alison D and de Mutsert, Ren{\'e}e and Orho-Melander, Marju and Owen, Katharine R and Perola, Markus and Peters, Annette and Province, Michael A and Rasheed, Asif and Ridker, Paul M and Rivadineira, Fernando and Rosendaal, Frits R and Rosengren, Anders H and Salomaa, Veikko and Sheu, Wayne H-H and Sladek, Rob and Smith, Blair H and Strauch, Konstantin and Uitterlinden, Andr{\'e} G and Varma, Rohit and Willer, Cristen J and Bl{\"u}her, Matthias and Butterworth, Adam S and Chambers, John Campbell and Chasman, Daniel I and Danesh, John and van Duijn, Cornelia and Dupuis, Jos{\'e}e and Franco, Oscar H and Franks, Paul W and Froguel, Philippe and Grallert, Harald and Groop, Leif and Han, Bok-Ghee and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Ingelsson, Erik and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal Singh and K{\"o}ttgen, Anna and Kuulasmaa, Kari and Laakso, Markku and Lin, Xu and Lind, Lars and Liu, Yongmei and Loos, Ruth J F and Marchini, Jonathan and Metspalu, Andres and Mook-Kanamori, Dennis and Nordestgaard, B{\o}rge G and Palmer, Colin N A and Pankow, James S and Pedersen, Oluf and Psaty, Bruce M and Rauramaa, Rainer and Sattar, Naveed and Schulze, Matthias B and Soranzo, Nicole and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Thorsteinsdottir, Unnur and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Wareham, Nicholas J and Wilson, James G and Zeggini, Eleftheria and Scott, Robert A and Barroso, In{\^e}s and Frayling, Timothy M and Goodarzi, Mark O and Meigs, James B and Boehnke, Michael and Saleheen, Danish and Morris, Andrew P and Rotter, Jerome I and McCarthy, Mark I} } @article {8491, title = {Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.}, journal = {Diabetes}, year = {2020}, month = {2020 Sep 11}, abstract = {

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

}, issn = {1939-327X}, doi = {10.2337/db20-0070}, author = {Yaghootkar, Hanieh and Zhang, Yiying and Spracklen, Cassandra N and Karaderi, Tugce and Huang, Lam Opal and Bradfield, Jonathan and Schurmann, Claudia and Fine, Rebecca S and Preuss, Michael H and Kutalik, Zolt{\'a}n and Wittemans, Laura Bl and Lu, Yingchang and Metz, Sophia and Willems, Sara M and Li-Gao, Ruifang and Grarup, Niels and Wang, Shuai and Molnos, Sophie and Sandoval-Z{\'a}rate, Am{\'e}rica A and Nalls, Mike A and Lange, Leslie A and Haesser, Jeffrey and Guo, Xiuqing and Lyytik{\"a}inen, Leo-Pekka and Feitosa, Mary F and Sitlani, Colleen M and Venturini, Cristina and Mahajan, Anubha and Kacprowski, Tim and Wang, Carol A and Chasman, Daniel I and Amin, Najaf and Broer, Linda and Robertson, Neil and Young, Kristin L and Allison, Matthew and Auer, Paul L and Bl{\"u}her, Matthias and Borja, Judith B and Bork-Jensen, Jette and Carrasquilla, Germ{\'a}n D and Christofidou, Paraskevi and Demirkan, Ayse and Doege, Claudia A and Garcia, Melissa E and Graff, Mariaelisa and Guo, Kaiying and Hakonarson, Hakon and Hong, Jaeyoung and Ida Chen, Yii-Der and Jackson, Rebecca and Jakupovi{\'c}, Hermina and Jousilahti, Pekka and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Kizer, Jorge R and Kriebel, Jennifer and LeDuc, Charles A and Li, Jin and Lind, Lars and Luan, Jian{\textquoteright}an and Mackey, David and Mangino, Massimo and M{\"a}nnist{\"o}, Satu and Martin Carli, Jayne F and Medina-G{\'o}mez, Carolina and Mook-Kanamori, Dennis O and Morris, Andrew P and de Mutsert, Ren{\'e}e and Nauck, Matthias and Nedeljkovic, Ivana and Pennell, Craig E and Pradhan, Arund D and Psaty, Bruce M and Raitakari, Olli T and Scott, Robert A and Skaaby, Tea and Strauch, Konstantin and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Wu, Ying and Yao, Jie and Walker, Mark and North, Kari E and Kovacs, Peter and Ikram, M Arfan and van Duijn, Cornelia M and Ridker, Paul M and Lye, Stephen and Homuth, Georg and Ingelsson, Erik and Spector, Tim D and McKnight, Barbara and Province, Michael A and Lehtim{\"a}ki, Terho and Adair, Linda S and Rotter, Jerome I and Reiner, Alexander P and Wilson, James G and Harris, Tamara B and Ripatti, Samuli and Grallert, Harald and Meigs, James B and Salomaa, Veikko and Hansen, Torben and Willems van Dijk, Ko and Wareham, Nicholas J and Grant, Struan Fa and Langenberg, Claudia and Frayling, Timothy M and Lindgren, Cecilia M and Mohlke, Karen L and Leibel, Rudolph L and Loos, Ruth Jf and Kilpel{\"a}inen, Tuomas O} }