A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

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.Peer reviewe

A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle

Over 40% of microRNAs (miRNAs) are located in introns of protein-coding genes, and many of these intronic miRNAs are co-regulated with their host genes(1,2). In such cases of co-regulation, the products of host genes and their intronic miRNAs can cooperate to coordinately regulate biologically important pathways(3,4). Therefore, we screened intronic miRNAs dysregulated in the livers of mouse models of obesity to identify previously uncharacterized protein-coding host genes that may contribute to the pathogenesis of obesity-associated insulin resistance and type 2 diabetes mellitus. Our approach revealed that expression of both the gene encoding ectodysplasin A (Eda), the causal gene in X-linked hypohidrotic ectodermal dysplasia (XLHED)(5), and its intronic miRNA, miR-676, was increased in the livers of obese mice. Moreover, hepatic EDA expression is increased in obese human subjects and reduced upon weight loss, and its hepatic expression correlates with systemic insulin resistance. We also found that reducing miR-676 expression in db/db mice increases the expression of proteins involved in fatty acid oxidation and reduces the expression of inflammatory signaling components in the liver. Further, we found that Eda expression in mouse liver is controlled via PPAR gamma and RXR-alpha, increases in circulation under conditions of obesity, and promotes JNK activation and inhibitory serine phosphorylation of IRS1 in skeletal muscle. In accordance with these findings, gain-and loss-of-function approaches reveal that liver-derived EDA regulates systemic glucose metabolism, suggesting that EDA is a hepatokine that can contribute to impaired skeletal muscle insulin sensitivity in obesity

Obesity-Induced CerS6-Dependent C-16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance

Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C-14:0 to C-30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C-16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6 D/D) mice exhibit reduced C-16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6 D/D mice, but also in brown adipose tissue-(CerS6 DBAT) and liver-specific (CerS6 DLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition

Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E-2 (PGE(2)) into the metabolite 15-keto PGE(2), was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PG E2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

none204Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.noneLagou V.; Magi R.; Hottenga J.-J.; Grallert H.; Perry J.R.B.; Bouatia-Naji N.; Marullo L.; Rybin D.; Jansen R.; Min J.L.; Dimas A.S.; Ulrich A.; Zudina L.; Gadin J.R.; Jiang L.; Faggian A.; Bonnefond A.; Fadista J.; Stathopoulou M.G.; Isaacs A.; Willems S.M.; Navarro P.; Tanaka T.; Jackson A.U.; Montasser M.E.; O'Connell J.R.; Bielak L.F.; Webster R.J.; Saxena R.; Stafford J.M.; Pourcain B.S.; Timpson N.J.; Salo P.; Shin S.-Y.; Amin N.; Smith A.V.; Li G.; Verweij N.; Goel A.; Ford I.; Johnson P.C.D.; Johnson T.; Kapur K.; Thorleifsson G.; Strawbridge R.J.; Rasmussen-Torvik L.J.; Esko T.; Mihailov E.; Fall T.; Fraser R.M.; Mahajan A.; Kanoni S.; Giedraitis V.; Kleber M.E.; Silbernagel G.; Meyer J.; Muller-Nurasyid M.; Ganna A.; Sarin A.-P.; Yengo L.; Shungin D.; Luan J.; Horikoshi M.; An P.; Sanna S.; Boettcher Y.; Rayner N.W.; Nolte I.M.; Zemunik T.; Iperen E.; Kovacs P.; Hastie N.D.; Wild S.H.; McLachlan S.; Campbell S.; Polasek O.; Carlson O.; Egan J.; Kiess W.; Willemsen G.; Kuusisto J.; Laakso M.; Dimitriou M.; Hicks A.A.; Rauramaa R.; Bandinelli S.; Thorand B.; Liu Y.; Miljkovic I.; Lind L.; Doney A.; Perola M.; Hingorani A.; Kivimaki M.; Kumari M.; Bennett A.J.; Groves C.J.; Herder C.; Koistinen H.A.; Kinnunen L.; Faire U.; Bakker S.J.L.; Uusitupa M.; Palmer C.N.A.; Jukema J.W.; Sattar N.; Pouta A.; Snieder H.; Boerwinkle E.; Pankow J.S.; Magnusson P.K.; Krus U.; Scapoli C.; de Geus E.J.C.N.; Bluher M.; Wolffenbuttel B.H.R.; Province M.A.; Abecasis G.R.; Meigs J.B.; Hovingh G.K.; Lindstrom J.; Wilson J.F.; Wright A.F.; Dedoussis G.V.; Bornstein S.R.; Schwarz P.E.H.; Tonjes A.; Winkelmann B.R.; Boehm B.O.; Marz W.; Metspalu A.; Price J.F.; Deloukas P.; Korner A.; Lakka T.A.; Keinanen-Kiukaanniemi S.M.; Saaristo T.E.; Bergman R.N.; Tuomilehto J.; Wareham N.J.; Langenberg C.; Mannisto S.; Franks P.W.; Hayward C.; Vitart V.; Kaprio J.; Visvikis-Siest S.; Balkau B.; Altshuler D.; Rudan I.; Stumvoll M.; Campbell H.; van Duijn C.M.; Gieger C.; Illig T.; Ferrucci L.; Pedersen N.L.; Pramstaller P.P.; Boehnke M.; Frayling T.M.; Shuldiner A.R.; Peyser P.A.; Kardia S.L.R.; Palmer L.J.; Penninx B.W.; Meneton P.; Harris T.B.; Navis G.; Harst P.; Smith G.D.; Forouhi N.G.; Loos R.J.F.; Salomaa V.; Soranzo N.; Boomsma D.I.; Groop L.; Tuomi T.; Hofman A.; Munroe P.B.; Gudnason V.; Siscovick D.S.; Watkins H.; Lecoeur C.; Vollenweider P.; Franco-Cereceda A.; Eriksson P.; Jarvelin M.-R.; Stefansson K.; Hamsten A.; Nicholson G.; Karpe F.; Dermitzakis E.T.; Lindgren C.M.; McCarthy M.I.; Froguel P.; Kaakinen M.A.; Lyssenko V.; Watanabe R.M.; Ingelsson E.; Florez J.C.; Dupuis J.; Barroso I.; Morris A.P.; Prokopenko I.Lagou, V.; Magi, R.; Hottenga, J. -J.; Grallert, H.; Perry, J. R. B.; Bouatia-Naji, N.; Marullo, L.; Rybin, D.; Jansen, R.; Min, J. L.; Dimas, A. S.; Ulrich, A.; Zudina, L.; Gadin, J. R.; Jiang, L.; Faggian, A.; Bonnefond, A.; Fadista, J.; Stathopoulou, M. G.; Isaacs, A.; Willems, S. M.; Navarro, P.; Tanaka, T.; Jackson, A. U.; Montasser, M. E.; O'Connell, J. R.; Bielak, L. F.; Webster, R. J.; Saxena, R.; Stafford, J. M.; Pourcain, B. S.; Timpson, N. J.; Salo, P.; Shin, S. -Y.; Amin, N.; Smith, A. V.; Li, G.; Verweij, N.; Goel, A.; Ford, I.; Johnson, P. C. D.; Johnson, T.; Kapur, K.; Thorleifsson, G.; Strawbridge, R. J.; Rasmussen-Torvik, L. J.; Esko, T.; Mihailov, E.; Fall, T.; Fraser, R. M.; Mahajan, A.; Kanoni, S.; Giedraitis, V.; Kleber, M. E.; Silbernagel, G.; Meyer, J.; Muller-Nurasyid, M.; Ganna, A.; Sarin, A. -P.; Yengo, L.; Shungin, D.; Luan, J.; Horikoshi, M.; An, P.; Sanna, S.; Boettcher, Y.; Rayner, N. W.; Nolte, I. M.; Zemunik, T.; Iperen, E.; Kovacs, P.; Hastie, N. D.; Wild, S. H.; Mclachlan, S.; Campbell, S.; Polasek, O.; Carlson, O.; Egan, J.; Kiess, W.; Willemsen, G.; Kuusisto, J.; Laakso, M.; Dimitriou, M.; Hicks, A. A.; Rauramaa, R.; Bandinelli, S.; Thorand, B.; Liu, Y.; Miljkovic, I.; Lind, L.; Doney, A.; Perola, M.; Hingorani, A.; Kivimaki, M.; Kumari, M.; Bennett, A. J.; Groves, C. J.; Herder, C.; Koistinen, H. A.; Kinnunen, L.; Faire, U.; Bakker, S. J. L.; Uusitupa, M.; Palmer, C. N. A.; Jukema, J. W.; Sattar, N.; Pouta, A.; Snieder, H.; Boerwinkle, E.; Pankow, J. S.; Magnusson, P. K.; Krus, U.; Scapoli, C.; de Geus, E. J. C. N.; Bluher, M.; Wolffenbuttel, B. H. R.; Province, M. A.; Abecasis, G. R.; Meigs, J. B.; Hovingh, G. K.; Lindstrom, J.; Wilson, J. F.; Wright, A. F.; Dedoussis, G. V.; Bornstein, S. R.; Schwarz, P. E. H.; Tonjes, A.; Winkelmann, B. R.; Boehm, B. O.; Marz, W.; Metspalu, A.; Price, J. F.; Deloukas, P.; Korner, A.; Lakka, T. A.; Keinanen-Kiukaanniemi, S. M.; Saaristo, T. E.; Bergman, R. N.; Tuomilehto, J.; Wareham, N. J.; Langenberg, C.; Mannisto, S.; Franks, P. W.; Hayward, C.; Vitart, V.; Kaprio, J.; Visvikis-Siest, S.; Balkau, B.; Altshuler, D.; Rudan, I.; Stumvoll, M.; Campbell, H.; van Duijn, C. M.; Gieger, C.; Illig, T.; Ferrucci, L.; Pedersen, N. L.; Pramstaller, P. P.; Boehnke, M.; Frayling, T. M.; Shuldiner, A. R.; Peyser, P. A.; Kardia, S. L. R.; Palmer, L. J.; Penninx, B. W.; Meneton, P.; Harris, T. B.; Navis, G.; Harst, P.; Smith, G. D.; Forouhi, N. G.; Loos, R. J. F.; Salomaa, V.; Soranzo, N.; Boomsma, D. I.; Groop, L.; Tuomi, T.; Hofman, A.; Munroe, P. B.; Gudnason, V.; Siscovick, D. S.; Watkins, H.; Lecoeur, C.; Vollenweider, P.; Franco-Cereceda, A.; Eriksson, P.; Jarvelin, M. -R.; Stefansson, K.; Hamsten, A.; Nicholson, G.; Karpe, F.; Dermitzakis, E. T.; Lindgren, C. M.; Mccarthy, M. I.; Froguel, P.; Kaakinen, M. A.; Lyssenko, V.; Watanabe, R. M.; Ingelsson, E.; Florez, J. C.; Dupuis, J.; Barroso, I.; Morris, A. P.; Prokopenko, I

The trans-ancestral genomic architecture of glycemic traits

Abstract Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body fat distribution

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants