%0 Journal Article %J Circ Cardiovasc Genet %D 2013 %T Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu %A Wu, Jason H Y %A Lemaitre, Rozenn N %A Manichaikul, Ani %A Guan, Weihua %A Tanaka, Toshiko %A Foy, Millennia %A Kabagambe, Edmond K %A Djoussé, Luc %A Siscovick, David %A Fretts, Amanda M %A Johnson, Catherine %A King, Irena B %A Psaty, Bruce M %A McKnight, Barbara %A Rich, Stephen S %A Chen, Yii-der I %A Nettleton, Jennifer A %A Tang, Weihong %A Bandinelli, Stefania %A Jacobs, David R %A Browning, Brian L %A Laurie, Cathy C %A Gu, Xiangjun %A Tsai, Michael Y %A Steffen, Lyn M %A Ferrucci, Luigi %A Fornage, Myriam %A Mozaffarian, Dariush %K Adult %K Aged %K Chromosomes, Human, Pair 2 %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K Fatty Acids, Monounsaturated %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Linkage Disequilibrium %K Lipogenesis %K Male %K Middle Aged %K Oleic Acid %K Palmitic Acid %K Polymorphism, Single Nucleotide %K Stearic Acids %X

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

%B Circ Cardiovasc Genet %V 6 %P 171-83 %8 2013 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract %R 10.1161/CIRCGENETICS.112.964619 %0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium. %A Guan, Weihua %A Steffen, Brian T %A Lemaitre, Rozenn N %A Wu, Jason H Y %A Tanaka, Toshiko %A Manichaikul, Ani %A Foy, Millennia %A Rich, Stephen S %A Wang, Lu %A Nettleton, Jennifer A %A Tang, Weihong %A Gu, Xiangjun %A Bandinelli, Stafania %A King, Irena B %A McKnight, Barbara %A Psaty, Bruce M %A Siscovick, David %A Djoussé, Luc %A Chen, Yii-Der Ida %A Ferrucci, Luigi %A Fornage, Myriam %A Mozafarrian, Dariush %A Tsai, Michael Y %A Steffen, Lyn M %K Adult %K Aged %K Aged, 80 and over %K Aging %K Chromosomes, Human, Pair 10 %K Chromosomes, Human, Pair 16 %K Chromosomes, Human, Pair 6 %K Fatty Acid Desaturases %K Fatty Acids, Omega-6 %K Female %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Prospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

%B Circ Cardiovasc Genet %V 7 %P 321-331 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24823311?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000208 %0 Journal Article %J J Lipid Res %D 2015 %T Genetic loci associated with circulating levels of very long-chain saturated fatty acids. %A Lemaitre, Rozenn N %A King, Irena B %A Kabagambe, Edmond K %A Wu, Jason H Y %A McKnight, Barbara %A Manichaikul, Ani %A Guan, Weihua %A Sun, Qi %A Chasman, Daniel I %A Foy, Millennia %A Wang, Lu %A Zhu, Jingwen %A Siscovick, David S %A Tsai, Michael Y %A Arnett, Donna K %A Psaty, Bruce M %A Djoussé, Luc %A Chen, Yii-der I %A Tang, Weihong %A Weng, Lu-Chen %A Wu, Hongyu %A Jensen, Majken K %A Chu, Audrey Y %A Jacobs, David R %A Rich, Stephen S %A Mozaffarian, Dariush %A Steffen, Lyn %A Rimm, Eric B %A Hu, Frank B %A Ridker, Paul M %A Fornage, Myriam %A Friedlander, Yechiel %K Cohort Studies %K Fatty Acids %K Genetic Loci %K Genetic Variation %K Genome-Wide Association Study %K Humans %X

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

%B J Lipid Res %V 56 %P 176-84 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25378659?dopt=Abstract %R 10.1194/jlr.M052456 %0 Journal Article %J Genome Biol %D 2016 %T DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. %A Ligthart, Symen %A Marzi, Carola %A Aslibekyan, Stella %A Mendelson, Michael M %A Conneely, Karen N %A Tanaka, Toshiko %A Colicino, Elena %A Waite, Lindsay L %A Joehanes, Roby %A Guan, Weihua %A Brody, Jennifer A %A Elks, Cathy %A Marioni, Riccardo %A Jhun, Min A %A Agha, Golareh %A Bressler, Jan %A Ward-Caviness, Cavin K %A Chen, Brian H %A Huan, Tianxiao %A Bakulski, Kelly %A Salfati, Elias L %A Fiorito, Giovanni %A Wahl, Simone %A Schramm, Katharina %A Sha, Jin %A Hernandez, Dena G %A Just, Allan C %A Smith, Jennifer A %A Sotoodehnia, Nona %A Pilling, Luke C %A Pankow, James S %A Tsao, Phil S %A Liu, Chunyu %A Zhao, Wei %A Guarrera, Simonetta %A Michopoulos, Vasiliki J %A Smith, Alicia K %A Peters, Marjolein J %A Melzer, David %A Vokonas, Pantel %A Fornage, Myriam %A Prokisch, Holger %A Bis, Joshua C %A Chu, Audrey Y %A Herder, Christian %A Grallert, Harald %A Yao, Chen %A Shah, Sonia %A McRae, Allan F %A Lin, Honghuang %A Horvath, Steve %A Fallin, Daniele %A Hofman, Albert %A Wareham, Nicholas J %A Wiggins, Kerri L %A Feinberg, Andrew P %A Starr, John M %A Visscher, Peter M %A Murabito, Joanne M %A Kardia, Sharon L R %A Absher, Devin M %A Binder, Elisabeth B %A Singleton, Andrew B %A Bandinelli, Stefania %A Peters, Annette %A Waldenberger, Melanie %A Matullo, Giuseppe %A Schwartz, Joel D %A Demerath, Ellen W %A Uitterlinden, André G %A van Meurs, Joyce B J %A Franco, Oscar H %A Chen, Yii-Der Ida %A Levy, Daniel %A Turner, Stephen T %A Deary, Ian J %A Ressler, Kerry J %A Dupuis, Josée %A Ferrucci, Luigi %A Ong, Ken K %A Assimes, Themistocles L %A Boerwinkle, Eric %A Koenig, Wolfgang %A Arnett, Donna K %A Baccarelli, Andrea A %A Benjamin, Emelia J %A Dehghan, Abbas %X

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

%B Genome Biol %V 17 %P 255 %8 2016 Dec 12 %G eng %N 1 %R 10.1186/s13059-016-1119-5 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Epigenetic Signatures of Cigarette Smoking. %A Joehanes, Roby %A Just, Allan C %A Marioni, Riccardo E %A Pilling, Luke C %A Reynolds, Lindsay M %A Mandaviya, Pooja R %A Guan, Weihua %A Xu, Tao %A Elks, Cathy E %A Aslibekyan, Stella %A Moreno-Macias, Hortensia %A Smith, Jennifer A %A Brody, Jennifer A %A Dhingra, Radhika %A Yousefi, Paul %A Pankow, James S %A Kunze, Sonja %A Shah, Sonia H %A McRae, Allan F %A Lohman, Kurt %A Sha, Jin %A Absher, Devin M %A Ferrucci, Luigi %A Zhao, Wei %A Demerath, Ellen W %A Bressler, Jan %A Grove, Megan L %A Huan, Tianxiao %A Liu, Chunyu %A Mendelson, Michael M %A Yao, Chen %A Kiel, Douglas P %A Peters, Annette %A Wang-Sattler, Rui %A Visscher, Peter M %A Wray, Naomi R %A Starr, John M %A Ding, Jingzhong %A Rodriguez, Carlos J %A Wareham, Nicholas J %A Irvin, Marguerite R %A Zhi, Degui %A Barrdahl, Myrto %A Vineis, Paolo %A Ambatipudi, Srikant %A Uitterlinden, André G %A Hofman, Albert %A Schwartz, Joel %A Colicino, Elena %A Hou, Lifang %A Vokonas, Pantel S %A Hernandez, Dena G %A Singleton, Andrew B %A Bandinelli, Stefania %A Turner, Stephen T %A Ware, Erin B %A Smith, Alicia K %A Klengel, Torsten %A Binder, Elisabeth B %A Psaty, Bruce M %A Taylor, Kent D %A Gharib, Sina A %A Swenson, Brenton R %A Liang, Liming %A DeMeo, Dawn L %A O'Connor, George T %A Herceg, Zdenko %A Ressler, Kerry J %A Conneely, Karen N %A Sotoodehnia, Nona %A Kardia, Sharon L R %A Melzer, David %A Baccarelli, Andrea A %A van Meurs, Joyce B J %A Romieu, Isabelle %A Arnett, Donna K %A Ong, Ken K %A Liu, Yongmei %A Waldenberger, Melanie %A Deary, Ian J %A Fornage, Myriam %A Levy, Daniel %A London, Stephanie J %X

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

%B Circ Cardiovasc Genet %V 9 %P 436-447 %8 2016 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.116.001506 %0 Journal Article %J Am J Clin Nutr %D 2016 %T 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. %A Ma, Yiyi %A Follis, Jack L %A Smith, Caren E %A Tanaka, Toshiko %A Manichaikul, Ani W %A Chu, Audrey Y %A Samieri, Cecilia %A Zhou, Xia %A Guan, Weihua %A Wang, Lu %A Biggs, Mary L %A Chen, Yii-der I %A Hernandez, Dena G %A Borecki, Ingrid %A Chasman, Daniel I %A Rich, Stephen S %A Ferrucci, Luigi %A Irvin, Marguerite Ryan %A Aslibekyan, Stella %A Zhi, Degui %A Tiwari, Hemant K %A Claas, Steven A %A Sha, Jin %A Kabagambe, Edmond K %A Lai, Chao-Qiang %A Parnell, Laurence D %A Lee, Yu-Chi %A Amouyel, Philippe %A Lambert, Jean-Charles %A Psaty, Bruce M %A King, Irena B %A Mozaffarian, Dariush %A McKnight, Barbara %A Bandinelli, Stefania %A Tsai, Michael Y %A Ridker, Paul M %A Ding, Jingzhong %A Mstat, Kurt Lohmant %A Liu, Yongmei %A Sotoodehnia, Nona %A Barberger-Gateau, Pascale %A Steffen, Lyn M %A Siscovick, David S %A Absher, Devin %A Arnett, Donna K %A Ordovas, Jose M %A Lemaitre, Rozenn N %K Apolipoproteins E %K ATP Binding Cassette Transporter 1 %K Cholesterol, HDL %K Cohort Studies %K Diet %K DNA Methylation %K Eicosapentaenoic Acid %K Epigenesis, Genetic %K Fatty Acids %K Gene Expression Regulation %K Humans %K Lipids %K Polymorphism, Single Nucleotide %K Promoter Regions, Genetic %K Triglycerides %X

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 × 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 × 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.

%B Am J Clin Nutr %V 103 %P 567-78 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract %R 10.3945/ajcn.115.112987 %0 Journal Article %J PLoS One %D 2017 %T Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Chasman, Daniel I %A Trompet, Stella %A Ahluwalia, Tarunveer S %A Teumer, Alexander %A Kleber, Marcus E %A Chen, Ming-Huei %A Wang, Jie Jin %A Attia, John R %A Marioni, Riccardo E %A Steri, Maristella %A Weng, Lu-Chen %A Pool, Rene %A Grossmann, Vera %A Brody, Jennifer A %A Venturini, Cristina %A Tanaka, Toshiko %A Rose, Lynda M %A Oldmeadow, Christopher %A Mazur, Johanna %A Basu, Saonli %A Frånberg, Mattias %A Yang, Qiong %A Ligthart, Symen %A Hottenga, Jouke J %A Rumley, Ann %A Mulas, Antonella %A de Craen, Anton J M %A Grotevendt, Anne %A Taylor, Kent D %A Delgado, Graciela E %A Kifley, Annette %A Lopez, Lorna M %A Berentzen, Tina L %A Mangino, Massimo %A Bandinelli, Stefania %A Morrison, Alanna C %A Hamsten, Anders %A Tofler, Geoffrey %A de Maat, Moniek P M %A Draisma, Harmen H M %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Lackner, Karl J %A Völker, Uwe %A McKnight, Barbara %A Huang, Jie %A Holliday, Elizabeth G %A McEvoy, Mark A %A Starr, John M %A Hysi, Pirro G %A Hernandez, Dena G %A Guan, Weihua %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Psaty, Bruce M %A Uitterlinden, André G %A de Geus, Eco J C %A Stott, David J %A Binder, Harald %A Hofman, Albert %A Franco, Oscar H %A Rotter, Jerome I %A Ferrucci, Luigi %A Spector, Tim D %A Deary, Ian J %A März, Winfried %A Greinacher, Andreas %A Wild, Philipp S %A Cucca, Francesco %A Boomsma, Dorret I %A Watkins, Hugh %A Tang, Weihong %A Ridker, Paul M %A Jukema, Jan W %A Scott, Rodney J %A Mitchell, Paul %A Hansen, Torben %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

%B PLoS One %V 12 %P e0167742 %8 2017 %G eng %N 1 %R 10.1371/journal.pone.0167742 %0 Journal Article %J J Lipid Res %D 2017 %T Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations. %A Hu, Yao %A Tanaka, Toshiko %A Zhu, Jingwen %A Guan, Weihua %A Wu, Jason H Y %A Psaty, Bruce M %A McKnight, Barbara %A King, Irena B %A Sun, Qi %A Richard, Melissa %A Manichaikul, Ani %A Frazier-Wood, Alexis C %A Kabagambe, Edmond K %A Hopkins, Paul N %A Ordovas, Jose M %A Ferrucci, Luigi %A Bandinelli, Stefania %A Arnett, Donna K %A Chen, Yii-der I %A Liang, Shuang %A Siscovick, David S %A Tsai, Michael Y %A Rich, Stephen S %A Fornage, Myriam %A Hu, Frank B %A Rimm, Eric B %A Jensen, Majken K %A Lemaitre, Rozenn N %A Mozaffarian, Dariush %A Steffen, Lyn M %A Morris, Andrew P %A Li, Huaixing %A Lin, Xu %X

Monounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 15,000 participants of Chinese- and European-ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor)>=8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor)>=61619;6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.

%B J Lipid Res %8 2017 Mar 15 %G eng %R 10.1194/jlr.P071860 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Boerwinkle, Eric %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Genet Epidemiol %D 2019 %T A large-scale exome array analysis of venous thromboembolism. %A Lindström, Sara %A Brody, Jennifer A %A Turman, Constance %A Germain, Marine %A Bartz, Traci M %A Smith, Erin N %A Chen, Ming-Huei %A Puurunen, Marja %A Chasman, Daniel %A Hassler, Jeffrey %A Pankratz, Nathan %A Basu, Saonli %A Guan, Weihua %A Gyorgy, Beata %A Ibrahim, Manal %A Empana, Jean-Philippe %A Olaso, Robert %A Jackson, Rebecca %A Braekkan, Sigrid K %A McKnight, Barbara %A Deleuze, Jean-Francois %A O'Donnell, Cristopher J %A Jouven, Xavier %A Frazer, Kelly A %A Psaty, Bruce M %A Wiggins, Kerri L %A Taylor, Kent %A Reiner, Alexander P %A Heckbert, Susan R %A Kooperberg, Charles %A Ridker, Paul %A Hansen, John-Bjarne %A Tang, Weihong %A Johnson, Andrew D %A Morange, Pierre-Emmanuel %A Trégouët, David A %A Kraft, Peter %A Smith, Nicholas L %A Kabrhel, Christopher %X

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.

%B Genet Epidemiol %8 2019 Jan 19 %G eng %R 10.1002/gepi.22187