@article {6617, title = {Gene-wide analysis detects two new susceptibility genes for Alzheimer{\textquoteright}s disease.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e94661}, abstract = {

BACKGROUND: Alzheimer{\textquoteright}s disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer{\textquoteright}s Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer{\textquoteright}s cases and 48,466 controls.

PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4{\texttimes}10-6) and 14 (IGHV1-67 p = 7.9{\texttimes}10-8) which indexed novel susceptibility loci.

SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer{\textquoteright}s disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer{\textquoteright}s disease.

}, keywords = {Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell}, issn = {1932-6203}, doi = {10.1371/journal.pone.0094661}, author = {Escott-Price, Valentina and Bellenguez, C{\'e}line and Wang, Li-San and Choi, Seung-Hoan and Harold, Denise and Jones, Lesley and Holmans, Peter and Gerrish, Amy and Vedernikov, Alexey and Richards, Alexander and DeStefano, Anita L and Lambert, Jean-Charles and Ibrahim-Verbaas, Carla A and Naj, Adam C and Sims, Rebecca and Jun, Gyungah and Bis, Joshua C and Beecham, Gary W and Grenier-Boley, Benjamin and Russo, Giancarlo and Thornton-Wells, Tricia A and Denning, Nicola and Smith, Albert V and Chouraki, Vincent and Thomas, Charlene and Ikram, M Arfan and Zelenika, Diana and Vardarajan, Badri N and Kamatani, Yoichiro and Lin, Chiao-Feng and Schmidt, Helena and Kunkle, Brian and Dunstan, Melanie L and Vronskaya, Maria and Johnson, Andrew D and Ruiz, Agustin and Bihoreau, Marie-Th{\'e}r{\`e}se and Reitz, Christiane and Pasquier, Florence and Hollingworth, Paul and Hanon, Olivier and Fitzpatrick, Annette L and Buxbaum, Joseph D and Campion, Dominique and Crane, Paul K and Baldwin, Clinton and Becker, Tim and Gudnason, Vilmundur and Cruchaga, Carlos and Craig, David and Amin, Najaf and Berr, Claudine and Lopez, Oscar L and De Jager, Philip L and Deramecourt, Vincent and Johnston, Janet A and Evans, Denis and Lovestone, Simon and Letenneur, Luc and Hernandez, Isabel and Rubinsztein, David C and Eiriksdottir, Gudny and Sleegers, Kristel and Goate, Alison M and Fi{\'e}vet, Nathalie and Huentelman, Matthew J and Gill, Michael and Brown, Kristelle and Kamboh, M Ilyas and Keller, Lina and Barberger-Gateau, Pascale and McGuinness, Bernadette and Larson, Eric B and Myers, Amanda J and Dufouil, Carole and Todd, Stephen and Wallon, David and Love, Seth and Rogaeva, Ekaterina and Gallacher, John and George-Hyslop, Peter St and Clarimon, Jordi and Lleo, Alberto and Bayer, Anthony and Tsuang, Debby W and Yu, Lei and Tsolaki, Magda and Boss{\`u}, Paola and Spalletta, Gianfranco and Proitsi, Petra and Collinge, John and Sorbi, Sandro and Garcia, Florentino Sanchez and Fox, Nick C and Hardy, John and Naranjo, Maria Candida Deniz and Bosco, Paolo and Clarke, Robert and Brayne, Carol and Galimberti, Daniela and Scarpini, Elio and Bonuccelli, Ubaldo and Mancuso, Michelangelo and Siciliano, Gabriele and Moebus, Susanne and Mecocci, Patrizia and Zompo, Maria Del and Maier, Wolfgang and Hampel, Harald and Pilotto, Alberto and Frank-Garc{\'\i}a, Ana and Panza, Francesco and Solfrizzi, Vincenzo and Caffarra, Paolo and Nacmias, Benedetta and Perry, William and Mayhaus, Manuel and Lannfelt, Lars and Hakonarson, Hakon and Pichler, Sabrina and Carrasquillo, Minerva M and Ingelsson, Martin and Beekly, Duane and Alvarez, Victoria and Zou, Fanggeng and Valladares, Otto and Younkin, Steven G and Coto, Eliecer and Hamilton-Nelson, Kara L and Gu, Wei and Razquin, Cristina and Pastor, Pau and Mateo, Ignacio and Owen, Michael J and Faber, Kelley M and Jonsson, Palmi V and Combarros, Onofre and O{\textquoteright}Donovan, Michael C and Cantwell, Laura B and Soininen, Hilkka and Blacker, Deborah and Mead, Simon and Mosley, Thomas H and Bennett, David A and Harris, Tamara B and Fratiglioni, Laura and Holmes, Clive and de Bruijn, Renee F A G and Passmore, Peter and Montine, Thomas J and Bettens, Karolien and Rotter, Jerome I and Brice, Alexis and Morgan, Kevin and Foroud, Tatiana M and Kukull, Walter A and Hannequin, Didier and Powell, John F and Nalls, Michael A and Ritchie, Karen and Lunetta, Kathryn L and Kauwe, John S K and Boerwinkle, Eric and Riemenschneider, Matthias and Boada, Merce and Hiltunen, Mikko and Martin, Eden R and Schmidt, Reinhold and Rujescu, Dan and Dartigues, Jean-Fran{\c c}ois and Mayeux, Richard and Tzourio, Christophe and Hofman, Albert and N{\"o}then, Markus M and Graff, Caroline and Psaty, Bruce M and Haines, Jonathan L and Lathrop, Mark and Pericak-Vance, Margaret A and Launer, Lenore J and Van Broeckhoven, Christine and Farrer, Lindsay A and van Duijn, Cornelia M and Ramirez, Alfredo and Seshadri, Sudha and Schellenberg, Gerard D and Amouyel, Philippe and Williams, Julie} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} }