%0 Journal Article %J Mol Psychiatry %D 2021 %T Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci. %A de Las Fuentes, Lisa %A Yun Ju Sung %A Noordam, Raymond %A Thomas W Winkler %A Feitosa, Mary F %A Schwander, Karen %A Bentley, Amy R %A Brown, Michael R %A Guo, Xiuqing %A Alisa Manning %A Daniel I Chasman %A Aschard, Hugues %A Traci M Bartz %A Bielak, Lawrence F %A Campbell, Archie %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Hartwig, Fernando P %A Horimoto, A R V R %A Li, Changwei %A Li-Gao, Ruifang %A Liu, Yongmei %A Marten, Jonathan %A Musani, Solomon K %A Ntalla, Ioanna %A Rankinen, Tuomo %A Melissa Richard %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Bamidele O Tayo %A Vojinovic, Dina %A Warren, Helen R %A Xuan, Deng %A Alver, Maris %A Boissel, Mathilde %A Jin-Fang Chai %A Chen, Xu %A Christensen, Kaare %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Giorgia G Girotto %A Sarah E Harris %A He, Meian %A Hsu, Fang-Chi %A Kühnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Rueedi, Rico %A Shu, Xiao-Ou %A Snieder, Harold %A Sofer, Tamar %A Takeuchi, Fumihiko %A Verweij, Niek %A Erin B Ware %A Weiss, Stefan %A Yanek, Lisa R %A Amin, Najaf %A Dan E Arking %A Donna K Arnett %A Bergmann, Sven %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Brumat, Marco %A Burke, Gregory %A Cabrera, Claudia P %A Canouil, Mickaël %A Chee, Miao Li %A Chen, Yii-Der Ida %A Cocca, Massimiliano %A Connell, John %A de Silva, H Janaka %A de Vries, Paul S %A Eiriksdottir, Gudny %A Jessica Faul %A Fisher, Virginia %A Forrester, Terrence %A Fox, Ervin F %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Tamara B Harris %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven %A Ikram, M Arfan %A Irvin, Marguerite R %A Kähönen, Mika %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Kraja, Aldi T %A Krieger, J E %A Langefeld, Carl D %A Li, Yize %A Liang, Jingjing %A David C Liewald %A Liu, Ching-Ti %A Liu, Jianjun %A Kurt Lohman %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Andres Metspalu %A Milaneschi, Yuri %A Lili Milani %A Dennis O Mook-Kanamori %A Michael A Nalls %A Nelson, Christopher P %A Norris, Jill M %A Jeff O'Connell %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmer, Nicholette D %A Nancy L Pedersen %A Thomas T Perls %A Peters, Annette %A Petersmann, Astrid %A Peyser, Patricia A %A Polasek, Ozren %A David J Porteous %A Raffel, Leslie J %A Rice, Treva K %A Rotter, Jerome I %A Rudan, Igor %A Rueda-Ochoa, Oscar-Leonel %A Sabanayagam, Charumathi %A Babatunde Salako %A Schreiner, Pamela J %A Shikany, James M %A Stephen Sidney %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A John M Starr %A Strauch, Konstantin %A Swertz, Morris A %A Teumer, Alexander %A Tham, Yih Chung %A André G Uitterlinden %A Vaidya, Dhananjay %A van der Ende, M Yldau %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya-Xing %A Wei, Wen-Bin %A David R Weir %A Wen, Wanqing %A Yao, Jie %A Yu, Bing %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Alan B Zonderman %A Becker, Diane M %A Bowden, Donald W %A Ian J Deary %A Dörr, Marcus %A Tõnu Esko %A Freedman, Barry I %A Froguel, Philippe %A Paolo P. Gasparini %A Gieger, Christian %A Jost Bruno Jonas %A Kammerer, Candace M %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Patrik K E Magnusson %A Marques-Vidal, Pedro %A Brenda W J H Penninx %A Nilesh J Samani %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Cooper, Richard S %A Correa, Adolfo %A Michele K Evans %A Gudnason, Vilmundur %A Caroline Hayward %A Horta, Bernardo L %A Tanika N Kelly %A Stephen B Kritchevsky %A Levy, Daniel %A Walter R Palmas %A Pereira, A C %A Province, Michael M %A Psaty, Bruce M %A Ridker, Paul M %A Charles N Rotimi %A Tai, E Shyong %A van Dam, Rob M %A Cornelia M van Duijn %A Wong, Tien Yin %A Kenneth Rice %A Gauderman, W James %A Alanna C Morrison %A Kari E North %A Sharon L R Kardia %A Caulfield, Mark J %A Elliott, Paul %A Munroe, Patricia B %A Franks, Paul W %A Rao, Dabeeru C %A Myriam Fornage %K Blood pressure %K Epistasis, Genetic %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Hypertension %K Polymorphism, Single Nucleotide %X

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

%B Mol Psychiatry %V 26 %P 2111-2125 %G eng %N 6 %R 10.1038/s41380-020-0719-3 %0 Journal Article %J Human Genetics and Genomics Advances %D 2021 %T Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits. %A Sun, Daokun %A Melissa Richard %A Musani, Solomon K %A Yun Ju Sung %A Thomas W Winkler %A Schwander, Karen %A Jin-Fang Chai %A Guo, Xiuqing %A Kilpeläinen, Tuomas O %A Vojinovic, Dina %A Aschard, Hugues %A Traci M Bartz %A Bielak, Lawrence F %A Brown, Michael R %A Chitrala, Kumaraswamy %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Liu, Yongmei %A Alisa Manning %A Noordam, Raymond %A Smith, Albert V %A Sarah E Harris %A Kühnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Rauramaa, Rainer %A van der Most, Peter J %A Wang, Rujia %A Erin B Ware %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Dan E Arking %A Donna K Arnett %A Barac, Ana %A Boerwinkle, Eric %A Broeckel, Ulrich %A Chakravarti, Aravinda %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A Davigulus, Martha L %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Vries, Paul S %A Delaney, Joseph A C %A Ana V Diez Roux %A Dörr, Marcus %A Jessica Faul %A Fretts, Amanda M %A Gallo, Linda C %A Hans-Jörgen Grabe %A Gu, C Charles %A Tamara B Harris %A Hartman, Catharina C A %A Heikkinen, Sami %A Ikram, M Arfan %A Isasi, Carmen %A Johnson, W Craig %A Jost Bruno Jonas %A Kaplan, Robert C %A Komulainen, Pirjo %A Krieger, Jose E %A Levy, Daniel %A Liu, Jianjun %A Kurt Lohman %A Luik, Annemarie I %A Martin, Lisa W %A Meitinger, Thomas %A Milaneschi, Yuri %A Jeff O'Connell %A Walter R Palmas %A Peters, Annette %A Peyser, Patricia A %A Pulkki-Raback, Laura %A Raffel, Leslie J %A Reiner, Alex P %A Kenneth Rice %A Robinson, Jennifer G %A Rosendaal, Frits R %A Schmidt, Carsten Oliver %A Schreiner, Pamela J %A Schwettmann, Lars %A Shikany, James M %A Shu, Xiao-Ou %A Stephen Sidney %A Sims, Mario %A Smith, Jennifer A %A Sotoodehnia, Nona %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent %A André G Uitterlinden %A Cornelia M van Duijn %A Waldenberger, Melanie %A Wee, Hwee-Lin %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Zeng, Donglin %A Zhao, Wei %A Zhu, Xiaofeng %A Alan B Zonderman %A Becker, Diane M %A Ian J Deary %A Gieger, Christian %A Lakka, Timo A %A Lehtimäki, Terho %A Kari E North %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Snieder, Harold %A Wang, Ya-Xing %A David R Weir %A Zheng, Wei %A Michele K Evans %A Gauderman, W James %A Gudnason, Vilmundur %A Horta, Bernardo L %A Liu, Ching-Ti %A Dennis O Mook-Kanamori %A Alanna C Morrison %A Pereira, Alexandre C %A Psaty, Bruce M %A Amin, Najaf %A Fox, Ervin R %A Charles Kooperberg %A Sim, Xueling %A Laura Bierut %A Rotter, Jerome I %A Sharon L R Kardia %A Franceschini, Nora %A Rao, Dabeeru C %A Myriam Fornage %K blood pressure traits %X

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

%B Human Genetics and Genomics Advances %V 2 %P 100013 %G eng %N 1 %R 10.1016/j.xhgg.2020.100013 %0 Journal Article %J Nature Communications %D 2019 %T Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. %A Kilpeläinen, Tuomas O %A Bentley, Amy R %A Noordam, Raymond %A Yun Ju Sung %A Schwander, Karen %A Thomas W Winkler %A Jakupović, Hermina %A Daniel I Chasman %A Alisa Manning %A Ntalla, Ioanna %A Aschard, Hugues %A Brown, Michael R %A de Las Fuentes, Lisa %A Franceschini, Nora %A Guo, Xiuqing %A Vojinovic, Dina %A Aslibekyan, Stella %A Feitosa, Mary F %A Kho, Minjung %A Musani, Solomon K %A Melissa Richard %A Wang, Heming %A Wang, Zhe %A Traci M Bartz %A Bielak, Lawrence F %A Campbell, Archie %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Li, Changwei %A Kurt Lohman %A Marten, Jonathan %A Sim, Xueling %A Smith, Albert V %A Tajuddin, Salman M %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Jin-Fang Chai %A Chen, Xu %A Divers, Jasmin %A Evangelou, Evangelos %A Gao, Chuan %A Graff, Mariaelisa %A Sarah E Harris %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Jing Hua Zhao %A Kraja, Aldi T %A Kühnel, Brigitte %A Laguzzi, Federica %A Lyytikäinen, Leo-Pekka %A Ilja M Nolte %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Rueedi, Rico %A Heather M Stringham %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Verweij, Niek %A Erin B Ware %A Wen, Wanqing %A Li, Xiaoyin %A Yanek, Lisa R %A Amin, Najaf %A Donna K Arnett %A Boerwinkle, Eric %A Brumat, Marco %A Brian E Cade %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Concas, Maria Pina %A Connell, John %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Demirkan, Ayse %A Ding, Jingzhong %A Charles B Eaton %A Jessica Faul %A Friedlander, Yechiel %A Gabriel, Kelley P %A Ghanbari, Mohsen %A Giulianini, Franco %A Gu, Chi Charles %A Gu, Dongfeng %A Tamara B Harris %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hunt, Steven C %A Ikram, M Arfan %A Jost Bruno Jonas %A Koh, Woon-Puay %A Komulainen, Pirjo %A Krieger, Jose E %A Stephen B Kritchevsky %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Lenore J Launer %A Leander, Karin %A Lemaitre, Rozenn N %A Lewis, Cora E %A Liang, Jingjing %A Liu, Jianjun %A Mägi, Reedik %A Manichaikul, Ani %A Meitinger, Thomas %A Andres Metspalu %A Milaneschi, Yuri %A Mohlke, Karen L %A Thomas H Mosley %A Murray, Alison D %A Michael A Nalls %A Nang, Ei-Ei Khaing %A Nelson, Christopher P %A Nona, Sotoodehnia %A Norris, Jill M %A Nwuba, Chiamaka Vivian %A Jeff O'Connell %A Palmer, Nicholette D %A Papanicolau, George J %A Pazoki, Raha %A Nancy L Pedersen %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A David J Porteous %A Poveda, Alaitz %A Olli T Raitakari %A Rich, Stephen S %A Neil Risch %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Schreiner, Pamela J %A Scott, Robert A %A Stephen Sidney %A Sims, Mario %A Smith, Jennifer A %A Snieder, Harold %A Sofer, Tamar %A John M Starr %A Sternfeld, Barbara %A Strauch, Konstantin %A Tang, Hua %A Kent D Taylor %A Tsai, Michael Y %A Tuomilehto, Jaakko %A André G Uitterlinden %A van der Ende, M Yldau %A van Heemst, Diana %A Voortman, Trudy %A Waldenberger, Melanie %A Wennberg, Patrik %A Wilson, Gregory %A Xiang, Yong-Bing %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Alan B Zonderman %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A de Faire, Ulf %A Ian J Deary %A Elliott, Paul %A Tõnu Esko %A Freedman, Barry I %A Froguel, Philippe %A Paolo P. Gasparini %A Gieger, Christian %A Kato, Norihiro %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Patrik K E Magnusson %A Oldehinkel, Albertine J %A Brenda W J H Penninx %A Nilesh J Samani %A Shu, Xiao-Ou %A van der Harst, Pim %A Jana V. van Vliet-Ostaptchouk %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wang, Ya X %A Wareham, Nicholas J %A David R Weir %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Michele K Evans %A Franks, Paul W %A Gudnason, Vilmundur %A Caroline Hayward %A Horta, Bernardo L %A Tanika N Kelly %A Liu, Yongmei %A Kari E North %A Pereira, Alexandre C %A Ridker, Paul M %A Tai, E Shyong %A van Dam, Rob M %A Fox, Ervin R %A Sharon L R Kardia %A Liu, Ching-Ti %A Dennis O Mook-Kanamori %A Province, Michael A %A Redline, Susan %A Cornelia M van Duijn %A Rotter, Jerome I %A Charles Kooperberg %A Gauderman, W James %A Psaty, Bruce M %A Kenneth Rice %A Munroe, Patricia B %A Myriam Fornage %A Cupples, L Adrienne %A Charles N Rotimi %A Alanna C Morrison %A Rao, Dabeeru C %A Ruth J F Loos %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Asians %K Blacks %K Brazil %K Calcium-Binding Proteins %K Cholesterol %K Cholesterol, HDL %K Cholesterol, LDL %K Exercise %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Hispanic or Latino %K Humans %K LIM-Homeodomain Proteins %K Lipid Metabolism %K Lipids %K Male %K Membrane Proteins %K Microtubule-Associated Proteins %K Middle Aged %K Muscle Proteins %K Nerve Tissue Proteins %K Transcription Factors %K Triglycerides %K Whites %K Young Adult %X

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

%B Nature Communications %V 10 %P 376 %G eng %N 1 %R 10.1038/s41467-018-08008-w