Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts

Background: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. Objective: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. Design: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86, 467) and EPA +DHA (n = 62, 265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. Results: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Telomere length in peripheral blood mononuclear cells is associated with folate status in men

Human chromosomes are capped by telomeres, which consist of tandem repeats of DNA and associated proteins. The length of the telomeres is reduced with increasing cell divisions except when the enzyme telomerase is active, as in stem cells and germ cells. Telomere dysfunction has been associated with development of age-related pathologies, including cancer, cardiovascular disease, Alzheimer's disease, and Parkinson's disease. DNA damage in the telomeric region causes attrition of telomeres. Because folate provides precursors for nucleotide synthesis and thus affects the integrity of DNA, including that of the telomeric region, folate status has the potential to influence telomere length. Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. In this study, we determined whether folate status and the 677C > T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene are associated with the telomere length of peripheral blood mononuclear cells in healthy men. The results of our study showed that plasma concentration of folate was associated with telomere length of peripheral blood mononuclear cells in a nonlinear manner. When plasma folate concentration was above the median, there was a positive relationship between folate and telomere length. In contrast, there was an inverse relationship between folate and telomere length when plasma folate concentration was below the median. The MTHFR 677C> T polymorphism was weakly associated (P = 0.065) with increased telomere length at below-median folate status. We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation

Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE consortium studies1-4

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesiumintake and fasting glucose and insulin. Fifteen studies fromthe CHARGE (Cohorts for Heart and Aging Research inGenomic Epidemiology) Consortiumprovided data fromup to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = 20.009 mmol/L (95% CI: 20.013, 20.005), P < 0.0001] and insulin [20.020 ln-pmol/L (95%CI:20.024,20.017), P < 0.0001].Nomagnesium-related SNP or interaction between any SNP andmagnesiumreached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with ot

Measurement of D+(s) and D*+(s) production in B meson decays and from continuum e+ e- annihilations at s**(1/2) = 10.6-GeV.

none622Bernard Aubert; D. Boutigny; J.M. Gaillard; A. Hicheur; Y. Karyotakis; J.P. Lees; P. Robbe; V. Tisserand; A. Palano; G.P. Chen; J.C. Chen; N.D. Qi; G. Rong; P. Wang; Y.S. Hz; G. Eigen; P.L. Reinertsen; B. Stugu; B. Abbott; G.S. Abrams; A.W. Borgland; A.B. Breon; David Nathan Brown; Janice Button-Shafer; R.N. Cahn; A.R. Clark; M.S. Gill; A.V. Gritsan; Y. Groysman; R.G. Jacobsen; R.W. Kadel; J. Kadyk; L.T. Kerth; S. Kluth; Yu.G. Kolomensky; J.F. Kral; C. LeClerc; M.E. Levi; T. Liu; G. Lynch; A.B. Meyer; M. Momayezi; P.J. Oddone; A. Perazzo; M. Pripstein; N.A. Roe; A. Romosan; M.T. Ronan; V.G. Shelkov; A.V. Telnov; W.A. Wenzel; P.G. Bright-Thomas; T.J. Harrison; C.M. Hawkes; D.J. Knowles; S.W. O'Neale; R.C. Penny; A.T. Watson; N.K Watson; T. Deppermann; K. Goetzen; H. Koch; J. Krug; M. Kunze; B. Lewandowski; K. Peters; H. Schmuecker; M. Steinke; J.C. Andress; N.R. Barlow; W. Bhimji; N. Chevalier; P.J. Clark; W.N. Cottingham; N. De Groot; N. Dyce; B. Foster; J.D. McFall; D. Wallom; F.F. Wilson; K. Abe; C. Hearty; T.S. Mattison; J.A. McKenna; D. Thiessen; S. Jolly; A.K. McKemey; Jane S. Tinslay; V.E. Blinov; A.D. Bukin; D.A. Bukin; A.R. Buzykaev; V.B. Golubev; V.N. Ivanchenko; A.A. Korol; E.A. Kravchenko; A.P. Onuchin; A.A. Salnikov; S.I. Serednyakov; Yu.I. Skovpen; Valery I. Telnov; A.N. Yushkov; D. Best; A.J. Lankford; M. Mandelkern; S. McMahon; D.P. Stoker; A. Ahsan; K. Arisaka; C. Buchanan; S. Chun; J.G. Branson; D.B. MacFarlane; Soeren A. Prell; S. Rahatlou; G. Raven; V. Sharma; C. Campagnari; B. Dahmes; P.A. Hart; N. Kuznetsova; S.L. Levy; O. Long; A. Lu; J.D. Richman; W. Verkerke; Michael S. Witherell; S. Yellin; J. Beringer; D.E. Dorfan; A.M. Eisner; A. Frey; A.A. Grillo; M. Grothe; C.A. Heusch; R.P. Johnson; W. Kroeger; William S. Lockman; T. Pulliam; H. Sadrozinski; T. Schalk; R.E. Schmitz; B.A. Schumm; A. Seiden; M. Turri; W. Walkowiak; D.C. Williams; M.G. Wison; E. Chen; G.P. Dubois-Felsmann; A. Dvoretskii; D.G. Hitlin; S. Metzler; J. Oyang; F.C. Porter; A. Ryd; A. Samuel; M. Weaver; S. Yang; R.Y. Zhu; S. Devmal; T.L. Geld; S. Jayatilleke; G. Mancinelli; B.T. Meadows; M.D. Sokoloff; T. Barillari; P. Bloom; M.O. Dima; S. Fahey; William T. Ford; D.R. Johnson; U. Nauenberg; A. Olivas; H. Park; P. Rankin; J. Roy; S. Sen; James G. Smith; W.C. van Hoek; D.L. Wagner; J. Blouw; John L. Harton; M. Krishnamurthy; A. Soffer; W.H. Toki; R.J. Wilson; J. Zhang; T. Brandt; J. Brose; T. Colberg; G. Dahlinger; M. Dickopp; R.S. Dubitzky; A. Hauke; E. Maly; R. Muller-Pfefferkorn; S. Otto; Klaus R. Schubert; R. Schwierz; B. Spaan; L. Wilden; L. Behr; Denis Bernard; 1; G.R. Bonneaud; F. Brochard; J. Cohen-Tanugi; S. Ferrag; E. Roussot; S. T'Jampens; C. Thiebaux; G. Vasileiadis; M. Verderi; A. Anjomshoaa; R. Bernet; A. Khan; D. Lavin; F. Muheim; S. Playfer; J.E. Swain; M. Falbo; C. Borean; C. Bozzi; S. Dittongo; M. Folegani; L. Piemontese; E. Treadwell; F. Anulli; R. Baldini-Ferroli; A. Calcaterra; R. de Sangro; D. Falciai; G. Finocchiaro; P. Patteri; I.M. Peruzzi; M. Piccolo; Y. Xie; A. Zallo; S. Bagnasco; A. Buzzo; R. Contri; G. Crosetti; P. Fabbricatore; S. Farinon; M. Lo Vetere; M. Macri; M.R. Monge; R. Musenich; M. Pallavicini; R. Parodi; S. Passaggio; F.C. Pastore; C. Patrignani; M.G. Pia; C. Priano; E. Robutti; A. Santroni; M. Morii; R. Bartoldus; T. Dignan; R. Hamilton; U. Mallik; J. Cochran; H.B. Crawley; P.A. Fischer; J. Lamsa; W.T. Meyer; E.I. Rosenberg; M. Benkebil; G. Grosdidier; C. Hast; Andreas Hocker; H.M. Lacker; S. Laplace; V. Lepeltier; A.M. Lutz; S. Plaszczynski; M.H. Schune; S. Trincaz-Duvoid; A. Valassi; G. Wormser; R.M. Bionta; V. Brigljevic; D.J. Lange; M. Mugge; X. Shi; K. van Bibber; T.J. Wenaus; D.M. Wright; C.R. Wuest; M. Carroll; J.R. Fry; E. Gabathuler; R. Gamet; M. George; M. Kay; D.J. Payne; R.J. Sloane; C. Touramanis; M.L. Aspinwall; D.A. Bowerman; Paul D. Dauncey; U. Egede; Ivo M. Gough Eschrich; N.J.W. Gunawardane; J.A. Nash; P. Sanders; D. Smith; D.E. Azzopardi; J.J. 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Sciacca; J.M. LoSecco; J.R.G. Alsmiller; T.A. Gabriel; T. Handler; J. Brau; R. Frey; M. Iwasaki; N.B. Sinev; David M. Strom; F. Colecchia; F. Dal Corso; A. Dorigo; F. Galeazzi; M. Margoni; G. Michelon; M. Morandin; M. Posocco; M. Rotondo; F. Simonetto; R. Stroili; E. Torassa; C. Voci; Maurice Benayoun; H. Briand; J. Chauveau; P. David; C. de la Vaissiere; L. Del Buono; O. Hamon; F. Le Diberder; P Leruste; J. Lory; L. Roos; J. Stark; S. Versille; P. Manfredi; V. Re; V. Speziali; E.D. Frank; Larry D. Gladney; Q.H. Guo; J.H. Panetta; C. Angelini; G. Batignani; S. Bettarini; M. Bondioli; M. Carpinelli; F. Forti; M.A. Giorgi; A. Lusiani; F. Martinez-Vidal; M. Morganti; N. Neri; E. Paoloni; M. Rama; G. Rizzo; F. Sandrelli; G. Simi; G. Triggiani; J. Walsh; M. Haire; D. Judd; K. Paick; L. Turnbull; D.E. Wagoner; J. Albert; C. Bula; P. Elmer; C. Lu; K.T. McDonald; V. Miftakov; S.F. Schaffner; A.J.S. Smith; A. Tumanov; E.W. Varnes; G. Cavoto; D. del Re; R. Faccini; F. Ferrarotto; F. Ferroni; K. Fratini; E. Lamanna; Emanuele Leonardi; M.A. Mazzoni; Silvio Morganti; G. Piredda; F. Safai Tehrani; M. Serra; C. Voena; S. Christ; R. Waldi; P.F. Jacques; M. Kalelkar; R.J. Plano; T. Adye; B. Franek; N.I. Geddes; G.P. Gopal; S.M. Xella; R. Aleksan; G. De Domenico; S. Emery; A. Gaidot; S.F. Ganzhur; P.F. Giraud; W. Kozanecki; M. Langer; G.W. London; B. Mayer; B. Serfass; G. Vasseur; C. Yeche; M. Zito; N. Copty; M.V. Purohit; H. Singh; F.X. Yumiceva; I. Adam; P.L. Anthony; D. Aston; K. Baird; J.P. Berger; Elliott D. Bloom; A.M. Boyarski; F. Bulos; G. Calderini; R. Claus; M.R. Convery; D.P. Coupal; D.H. Coward; J. Dorfan; M. Doser; W. Dunwoodie; R.C. Field; T. Glanzman; G.L. Godfrey; S.J. Gowdy; P. Grosso; T. Himel; Tetiana Berger-Hryn'ova; M.E. Huffer; Walter R. Innes; C.P. Jessop; M.H. Kelsey; P. Kim; M.L. Kocian; Urs Langenegger; David W.G.S. Leith; S. Luitz; V. Luth; H.L. Lynch; H. Marsiske; S. Menke; R. Messner; K.C. Moffeit; R. Mount; D.R. Muller; C.P. O'Grady; M. Perl; S. Petrak; Helen R. Quinn; B.N. Ratcliff; S.H. Robertson; L.S. Rochester; A. Roodman; T. Schietinger; R.H. Schindler; J. Schwiening; V.V. Serbo; A. Snyder; A. Soha; S.M. Spanier; J. Stelzer; D. Su; M.K. Sullivan; H.A. Tanaka; J. Va'vra; S.R. Wagner; A.J.R. Weinstein; William J. Wisniewski; D.H. Wright; C.C. Young; P.R. Burchat; C.H. Cheng; David P. Kirkby; T.I. Meyer; C. Roat; R. Henderson; W. Bugg; H. Cohn; A.W. Weidemann; J.M. Izen; I. Kitayama; X.C. Lou; m. Turcotte; F. Bianchi; Marcella Bona; B. Di Girolamo; D. Gamba; A. Smol; D. Zanin; L. Bosisio; G. Della Ricca; L. Lanceri; A. Pompili; P. Poropat; M. Prest; E. Vallazza; G. Vuagnin; R.S. Panvini; C. Brown; Asoka S. De Silva; Robert V. Kowalewski; J.M. Roney; H.R. Band; E. Charles; S. Dasu; F. Di Lodovico; A.M. Eichenbaum; H. Hu; J.R. Johnson; R. Liu; J. Nielsen; Y. Pan; R. Prepost; I.J. Scott; J.H. von Wimmersperg-Toeller; S.L. Wu; Z. Yu; H. Zobernig; T.M.B. Kordich; H. NealBernard, Aubert; D., Boutigny; J. M., Gaillard; A., Hicheur; Y., Karyotakis; J. P., Lees; P., Robbe; V., Tisserand; A., Palano; G. P., Chen; J. C., Chen; N. D., Qi; G., Rong; P., Wang; Y. S., Hz; G., Eigen; P. L., Reinertsen; B., Stugu; B., Abbott; G. S., Abrams; A. W., Borgland; A. B., Breon; David Nathan, Brown; Janice Button, Shafer; R. N., Cahn; A. R., Clark; M. S., Gill; A. V., Gritsan; Y., Groysman; R. G., Jacobsen; R. W., Kadel; J., Kadyk; L. T., Kerth; S., Kluth; Kolomensky, Y. u. G.; J. F., Kral; C., Leclerc; M. E., Levi; T., Liu; G., Lynch; A. B., Meyer; M., Momayezi; P. J., Oddone; A., Perazzo; M., Pripstein; N. A., Roe; A., Romosan; M. T., Ronan; V. G., Shelkov; A. V., Telnov; W. A., Wenzel; P. G., Bright Thomas; T. J., Harrison; C. M., Hawkes; D. J., Knowles; S. W., O'Neale; R. C., Penny; A. T., Watson; N. K., Watson; T., Deppermann; K., Goetzen; H., Koch; J., Krug; M., Kunze; B., Lewandowski; K., Peters; H., Schmuecker; M., Steinke; J. C., Andress; N. R., Barlow; W., Bhimji; N., Chevalier; P. J., Clark; W. N., Cottingham; N., De Groot; N., Dyce; B., Foster; J. D., Mcfall; D., Wallom; F. F., Wilson; K., Abe; C., Hearty; T. S., Mattison; J. A., Mckenna; D., Thiessen; S., Jolly; A. K., Mckemey; Jane S., Tinslay; V. E., Blinov; A. D., Bukin; D. A., Bukin; A. R., Buzykaev; V. B., Golubev; V. N., Ivanchenko; A. A., Korol; E. A., Kravchenko; A. P., Onuchin; A. A., Salnikov; S. I., Serednyakov; Skovpen, Y. u. I.; Valery I., Telnov; A. N., Yushkov; D., Best; A. J., Lankford; M., Mandelkern; S., Mcmahon; D. P., Stoker; A., Ahsan; K., Arisaka; C., Buchanan; S., Chun; J. G., Branson; D. B., Macfarlane; Soeren A., Prell; S., Rahatlou; G., Raven; V., Sharma; C., Campagnari; B., Dahmes; P. A., Hart; N., Kuznetsova; S. L., Levy; O., Long; A., Lu; J. D., Richman; W., Verkerke; Michael S., Witherell; S., Yellin; J., Beringer; D. E., Dorfan; A. M., Eisner; A., Frey; A. A., Grillo; M., Grothe; C. A., Heusch; R. P., Johnson; W., Kroeger; William S., Lockman; T., Pulliam; H., Sadrozinski; T., Schalk; R. E., Schmitz; B. A., Schumm; A., Seiden; M., Turri; W., Walkowiak; D. C., Williams; M. G., Wison; E., Chen; G. P., Dubois Felsmann; A., Dvoretskii; D. G., Hitlin; S., Metzler; J., Oyang; F. C., Porter; A., Ryd; A., Samuel; M., Weaver; S., Yang; R. Y., Zhu; S., Devmal; T. L., Geld; S., Jayatilleke; G., Mancinelli; B. T., Meadows; M. D., Sokoloff; T., Barillari; P., Bloom; M. O., Dima; S., Fahey; William T., Ford; D. R., Johnson; U., Nauenberg; A., Olivas; H., Park; P., Rankin; J., Roy; S., Sen; James G., Smith; W. C., van Hoek; D. L., Wagner; J., Blouw; John L., Harton; M., Krishnamurthy; A., Soffer; W. H., Toki; R. J., Wilson; J., Zhang; T., Brandt; J., Brose; T., Colberg; G., Dahlinger; M., Dickopp; R. S., Dubitzky; A., Hauke; E., Maly; R., Muller Pfefferkorn; S., Otto; Klaus R., Schubert; R., Schwierz; B., Spaan; L., Wilden; L., Behr; Denis, Bernard; 1, ; G. R., Bonneaud; F., Brochard; J., Cohen Tanugi; S., Ferrag; E., Roussot; S., T'Jampens; C., Thiebaux; G., Vasileiadis; M., Verderi; A., Anjomshoaa; R., Bernet; A., Khan; D., Lavin; F., Muheim; S., Playfer; J. E., Swain; M., Falbo; C., Borean; C., Bozzi; S., Dittongo; M., Folegani; L., Piemontese; E., Treadwell; F., Anulli; R., Baldini Ferroli; A., Calcaterra; R., de Sangro; D., Falciai; G., Finocchiaro; P., Patteri; I. M., Peruzzi; M., Piccolo; Y., Xie; A., Zallo; S., Bagnasco; A., Buzzo; Contri, Roberto; G., Crosetti; P., Fabbricatore; S., Farinon; LO VETERE, Maurizio; M., Macri; Monge, MARIA ROBERTA; R., Musenich; Pallavicini, Marco; R., Parodi; S., Passaggio; F. C., Pastore; Patrignani, Claudia; M. G., Pia; C., Priano; E., Robutti; Santroni, Alberto; M., Morii; R., Bartoldus; T., Dignan; R., Hamilton; U., Mallik; J., Cochran; H. B., Crawley; P. A., Fischer; J., Lamsa; W. T., Meyer; E. I., Rosenberg; M., Benkebil; G., Grosdidier; C., Hast; Andreas, Hocker; H. M., Lacker; S., Laplace; V., Lepeltier; A. M., Lutz; S., Plaszczynski; M. H., Schune; S., Trincaz Duvoid; A., Valassi; G., Wormser; R. M., Bionta; V., Brigljevic; D. J., Lange; M., Mugge; X., Shi; K., van Bibber; T. J., Wenaus; D. M., Wright; C. R., Wuest; M., Carroll; J. R., Fry; E., Gabathuler; R., Gamet; M., George; M., Kay; D. J., Payne; R. J., Sloane; C., Touramanis; M. L., Aspinwall; D. A., Bowerman; Paul D., Dauncey; U., Egede; Ivo M., Gough Eschrich; N. J. W., Gunawardane; J. A., Nash; P., Sanders; D., Smith; D. E., Azzopardi; J. J., Back; P., Dixon; P. F., Harrison; R. J. L., Potter; H. W., Shorthouse; P., Strother; P. B., Vidal; M. I., Williams; G., Cowan; S., George; M. G., Green; A., Kurup; C. E., Marker; P., Mcgrath; T. R., Mcmahon; S., Ricciardi; F., Salvatore; I., Scott; G., Vaitsas; David Norvil, Brown; C. L., Davis; John, Allison; Roger J., Barlow; J. T., Boyd; A. C., Forti; J., Fullwood; F., Jackson; G. D., Lafferty; N., Savvas; E. T., Simopoulos; J. H., Weatherall; A., Farbin; A., Jawahery; V., Lillard; J., Olsen; D. A., Roberts; J. R., Schieck; G., Blaylock; C., Dallapiccola; K. T., Flood; Stanley S., Hertzbach; R., Kofler; T. B., Moore; H., Staengle; Stephane, Willocq; B., Brau; R., Cowan; G., Sciolla; F., Taylor; R. K., Yamamoto; M., Milek; P. M., Patel; J., Trischuk; F., Lanni; F., Palombo; J. M., Bauer; M., Booke; L., Cremaldi; V., Eschenburg; R., Kroeger; J., Reidy; D. A., Sanders; D. J., Summers; J. P., Martin; J. Y., Nief; R., Seitz; P., Taras; A., Woch; V., Zacek; H., Nicholson; C. S., Sutton; C., Cartaro; N., Cavallo; G., De Nardo; F., Fabozzi; C., Gatto; L., Lista; P., Paolucci; D., Piccolo; C., Sciacca; J. M., Losecco; J. R. G., Alsmiller; T. A., Gabriel; T., Handler; J., Brau; R., Frey; M., Iwasaki; N. 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Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation