%0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J Biol Psychiatry %D 2015 %T Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. %A Debette, Stephanie %A Ibrahim Verbaas, Carla A %A Bressler, Jan %A Schuur, Maaike %A Smith, Albert %A Bis, Joshua C %A Davies, Gail %A Wolf, Christiane %A Gudnason, Vilmundur %A Chibnik, Lori B %A Yang, Qiong %A DeStefano, Anita L %A de Quervain, Dominique J F %A Srikanth, Velandai %A Lahti, Jari %A Grabe, Hans J %A Smith, Jennifer A %A Priebe, Lutz %A Yu, Lei %A Karbalai, Nazanin %A Hayward, Caroline %A Wilson, James F %A Campbell, Harry %A Petrovic, Katja %A Fornage, Myriam %A Chauhan, Ganesh %A Yeo, Robin %A Boxall, Ruth %A Becker, James %A Stegle, Oliver %A Mather, Karen A %A Chouraki, Vincent %A Sun, Qi %A Rose, Lynda M %A Resnick, Susan %A Oldmeadow, Christopher %A Kirin, Mirna %A Wright, Alan F %A Jonsdottir, Maria K %A Au, Rhoda %A Becker, Albert %A Amin, Najaf %A Nalls, Mike A %A Turner, Stephen T %A Kardia, Sharon L R %A Oostra, Ben %A Windham, Gwen %A Coker, Laura H %A Zhao, Wei %A Knopman, David S %A Heiss, Gerardo %A Griswold, Michael E %A Gottesman, Rebecca F %A Vitart, Veronique %A Hastie, Nicholas D %A Zgaga, Lina %A Rudan, Igor %A Polasek, Ozren %A Holliday, Elizabeth G %A Schofield, Peter %A Choi, Seung Hoan %A Tanaka, Toshiko %A An, Yang %A Perry, Rodney T %A Kennedy, Richard E %A Sale, Michèle M %A Wang, Jing %A Wadley, Virginia G %A Liewald, David C %A Ridker, Paul M %A Gow, Alan J %A Pattie, Alison %A Starr, John M %A Porteous, David %A Liu, Xuan %A Thomson, Russell %A Armstrong, Nicola J %A Eiriksdottir, Gudny %A Assareh, Arezoo A %A Kochan, Nicole A %A Widen, Elisabeth %A Palotie, Aarno %A Hsieh, Yi-Chen %A Eriksson, Johan G %A Vogler, Christian %A van Swieten, John C %A Shulman, Joshua M %A Beiser, Alexa %A Rotter, Jerome %A Schmidt, Carsten O %A Hoffmann, Wolfgang %A Nöthen, Markus M %A Ferrucci, Luigi %A Attia, John %A Uitterlinden, André G %A Amouyel, Philippe %A Dartigues, Jean-François %A Amieva, Hélène %A Räikkönen, Katri %A Garcia, Melissa %A Wolf, Philip A %A Hofman, Albert %A Longstreth, W T %A Psaty, Bruce M %A Boerwinkle, Eric %A DeJager, Philip L %A Sachdev, Perminder S %A Schmidt, Reinhold %A Breteler, Monique M B %A Teumer, Alexander %A Lopez, Oscar L %A Cichon, Sven %A Chasman, Daniel I %A Grodstein, Francine %A Müller-Myhsok, Bertram %A Tzourio, Christophe %A Papassotiropoulos, Andreas %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Mosley, Thomas H %K Aged %K Aged, 80 and over %K Aging %K Apolipoproteins E %K Claudin-5 %K Cohort Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Memory Disorders %K Middle Aged %K Polymorphism, Single Nucleotide %K Proteins %K Proteoglycans %K Regression Analysis %K Sulfotransferases %K Verbal Learning %X

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

%B Biol Psychiatry %V 77 %P 749-63 %8 2015 Apr 15 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract %R 10.1016/j.biopsych.2014.08.027 %0 Journal Article %J Circ Cardiovasc Genet %D 2015 %T Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI. %A Verhaaren, Benjamin F J %A Debette, Stephanie %A Bis, Joshua C %A Smith, Jennifer A %A Ikram, M Kamran %A Adams, Hieab H %A Beecham, Ashley H %A Rajan, Kumar B %A Lopez, Lorna M %A Barral, Sandra %A van Buchem, Mark A %A van der Grond, Jeroen %A Smith, Albert V %A Hegenscheid, Katrin %A Aggarwal, Neelum T %A de Andrade, Mariza %A Atkinson, Elizabeth J %A Beekman, Marian %A Beiser, Alexa S %A Blanton, Susan H %A Boerwinkle, Eric %A Brickman, Adam M %A Bryan, R Nick %A Chauhan, Ganesh %A Chen, Christopher P L H %A Chouraki, Vincent %A de Craen, Anton J M %A Crivello, Fabrice %A Deary, Ian J %A Deelen, Joris %A De Jager, Philip L %A Dufouil, Carole %A Elkind, Mitchell S V %A Evans, Denis A %A Freudenberger, Paul %A Gottesman, Rebecca F %A Guðnason, Vilmundur %A Habes, Mohamad %A Heckbert, Susan R %A Heiss, Gerardo %A Hilal, Saima %A Hofer, Edith %A Hofman, Albert %A Ibrahim-Verbaas, Carla A %A Knopman, David S %A Lewis, Cora E %A Liao, Jiemin %A Liewald, David C M %A Luciano, Michelle %A van der Lugt, Aad %A Martinez, Oliver O %A Mayeux, Richard %A Mazoyer, Bernard %A Nalls, Mike %A Nauck, Matthias %A Niessen, Wiro J %A Oostra, Ben A %A Psaty, Bruce M %A Rice, Kenneth M %A Rotter, Jerome I %A von Sarnowski, Bettina %A Schmidt, Helena %A Schreiner, Pamela J %A Schuur, Maaike %A Sidney, Stephen S %A Sigurdsson, Sigurdur %A Slagboom, P Eline %A Stott, David J M %A van Swieten, John C %A Teumer, Alexander %A Töglhofer, Anna Maria %A Traylor, Matthew %A Trompet, Stella %A Turner, Stephen T %A Tzourio, Christophe %A Uh, Hae-Won %A Uitterlinden, André G %A Vernooij, Meike W %A Wang, Jing J %A Wong, Tien Y %A Wardlaw, Joanna M %A Windham, B Gwen %A Wittfeld, Katharina %A Wolf, Christiane %A Wright, Clinton B %A Yang, Qiong %A Zhao, Wei %A Zijdenbos, Alex %A Jukema, J Wouter %A Sacco, Ralph L %A Kardia, Sharon L R %A Amouyel, Philippe %A Mosley, Thomas H %A Longstreth, W T %A DeCarli, Charles C %A van Duijn, Cornelia M %A Schmidt, Reinhold %A Launer, Lenore J %A Grabe, Hans J %A Seshadri, Sudha S %A Ikram, M Arfan %A Fornage, Myriam %K Aged %K Aged, 80 and over %K Chromosomes, Human %K Continental Population Groups %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Middle Aged %K Models, Genetic %K Stroke %K White Matter %X

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

%B Circ Cardiovasc Genet %V 8 %P 398-409 %8 2015 Apr %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/25663218?dopt=Abstract %R 10.1161/CIRCGENETICS.114.000858 %0 Journal Article %J Stroke %D 2015 %T White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. %A Hofer, Edith %A Cavalieri, Margherita %A Bis, Joshua C %A DeCarli, Charles %A Fornage, Myriam %A Sigurdsson, Sigurdur %A Srikanth, Velandai %A Trompet, Stella %A Verhaaren, Benjamin F J %A Wolf, Christiane %A Yang, Qiong %A Adams, Hieab H H %A Amouyel, Philippe %A Beiser, Alexa %A Buckley, Brendan M %A Callisaya, Michele %A Chauhan, Ganesh %A de Craen, Anton J M %A Dufouil, Carole %A van Duijn, Cornelia M %A Ford, Ian %A Freudenberger, Paul %A Gottesman, Rebecca F %A Gudnason, Vilmundur %A Heiss, Gerardo %A Hofman, Albert %A Lumley, Thomas %A Martinez, Oliver %A Mazoyer, Bernard %A Moran, Chris %A Niessen, Wiro J %A Phan, Thanh %A Psaty, Bruce M %A Satizabal, Claudia L %A Sattar, Naveed %A Schilling, Sabrina %A Shibata, Dean K %A Slagboom, P Eline %A Smith, Albert %A Stott, David J %A Taylor, Kent D %A Thomson, Russell %A Töglhofer, Anna M %A Tzourio, Christophe %A van Buchem, Mark %A Wang, Jing %A Westendorp, Rudi G J %A Windham, B Gwen %A Vernooij, Meike W %A Zijdenbos, Alex %A Beare, Richard %A Debette, Stephanie %A Ikram, M Arfan %A Jukema, J Wouter %A Launer, Lenore J %A Longstreth, W T %A Mosley, Thomas H %A Seshadri, Sudha %A Schmidt, Helena %A Schmidt, Reinhold %K Adult %K Aged %K Cohort Studies %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Leukoencephalopathies %K Male %K Middle Aged %K Prospective Studies %K White Matter %X

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

%B Stroke %V 46 %P 3048-57 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract %R 10.1161/STROKEAHA.115.009252 %0 Journal Article %J Nat Genet %D 2017 %T Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. %A Christophersen, Ingrid E %A Rienstra, Michiel %A Roselli, Carolina %A Yin, Xiaoyan %A Geelhoed, Bastiaan %A Barnard, John %A Lin, Honghuang %A Arking, Dan E %A Smith, Albert V %A Albert, Christine M %A Chaffin, Mark %A Tucker, Nathan R %A Li, Molong %A Klarin, Derek %A Bihlmeyer, Nathan A %A Low, Siew-Kee %A Weeke, Peter E %A Müller-Nurasyid, Martina %A Smith, J Gustav %A Brody, Jennifer A %A Niemeijer, Maartje N %A Dörr, Marcus %A Trompet, Stella %A Huffman, Jennifer %A Gustafsson, Stefan %A Schurmann, Claudia %A Kleber, Marcus E %A Lyytikäinen, Leo-Pekka %A Seppälä, Ilkka %A Malik, Rainer %A Horimoto, Andrea R V R %A Perez, Marco %A Sinisalo, Juha %A Aeschbacher, Stefanie %A Thériault, Sébastien %A Yao, Jie %A Radmanesh, Farid %A Weiss, Stefan %A Teumer, Alexander %A Choi, Seung Hoan %A Weng, Lu-Chen %A Clauss, Sebastian %A Deo, Rajat %A Rader, Daniel J %A Shah, Svati H %A Sun, Albert %A Hopewell, Jemma C %A Debette, Stephanie %A Chauhan, Ganesh %A Yang, Qiong %A Worrall, Bradford B %A Paré, Guillaume %A Kamatani, Yoichiro %A Hagemeijer, Yanick P %A Verweij, Niek %A Siland, Joylene E %A Kubo, Michiaki %A Smith, Jonathan D %A Van Wagoner, David R %A Bis, Joshua C %A Perz, Siegfried %A Psaty, Bruce M %A Ridker, Paul M %A Magnani, Jared W %A Harris, Tamara B %A Launer, Lenore J %A Shoemaker, M Benjamin %A Padmanabhan, Sandosh %A Haessler, Jeffrey %A Bartz, Traci M %A Waldenberger, Melanie %A Lichtner, Peter %A Arendt, Marina %A Krieger, Jose E %A Kähönen, Mika %A Risch, Lorenz %A Mansur, Alfredo J %A Peters, Annette %A Smith, Blair H %A Lind, Lars %A Scott, Stuart A %A Lu, Yingchang %A Bottinger, Erwin B %A Hernesniemi, Jussi %A Lindgren, Cecilia M %A Wong, Jorge A %A Huang, Jie %A Eskola, Markku %A Morris, Andrew P %A Ford, Ian %A Reiner, Alex P %A Delgado, Graciela %A Chen, Lin Y %A Chen, Yii-Der Ida %A Sandhu, Roopinder K %A Li, Man %A Boerwinkle, Eric %A Eisele, Lewin %A Lannfelt, Lars %A Rost, Natalia %A Anderson, Christopher D %A Taylor, Kent D %A Campbell, Archie %A Magnusson, Patrik K %A Porteous, David %A Hocking, Lynne J %A Vlachopoulou, Efthymia %A Pedersen, Nancy L %A Nikus, Kjell %A Orho-Melander, Marju %A Hamsten, Anders %A Heeringa, Jan %A Denny, Joshua C %A Kriebel, Jennifer %A Darbar, Dawood %A Newton-Cheh, Christopher %A Shaffer, Christian %A Macfarlane, Peter W %A Heilmann-Heimbach, Stefanie %A Almgren, Peter %A Huang, Paul L %A Sotoodehnia, Nona %A Soliman, Elsayed Z %A Uitterlinden, André G %A Hofman, Albert %A Franco, Oscar H %A Völker, Uwe %A Jöckel, Karl-Heinz %A Sinner, Moritz F %A Lin, Henry J %A Guo, Xiuqing %A Dichgans, Martin %A Ingelsson, Erik %A Kooperberg, Charles %A Melander, Olle %A Loos, Ruth J F %A Laurikka, Jari %A Conen, David %A Rosand, Jonathan %A van der Harst, Pim %A Lokki, Marja-Liisa %A Kathiresan, Sekar %A Pereira, Alexandre %A Jukema, J Wouter %A Hayward, Caroline %A Rotter, Jerome I %A März, Winfried %A Lehtimäki, Terho %A Stricker, Bruno H %A Chung, Mina K %A Felix, Stephan B %A Gudnason, Vilmundur %A Alonso, Alvaro %A Roden, Dan M %A Kääb, Stefan %A Chasman, Daniel I %A Heckbert, Susan R %A Benjamin, Emelia J %A Tanaka, Toshihiro %A Lunetta, Kathryn L %A Lubitz, Steven A %A Ellinor, Patrick T %X

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

%B Nat Genet %V 49 %P 946-952 %8 2017 Jun %G eng %N 6 %R 10.1038/ng.3843 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Jarvelin, Marjo-Riitta %A Johansson, Asa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stephanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

%B Hypertension %8 2017 Jul 24 %G eng %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Stroke %D 2018 %T Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. %A Jian, Xueqiu %A Satizabal, Claudia L %A Smith, Albert V %A Wittfeld, Katharina %A Bis, Joshua C %A Smith, Jennifer A %A Hsu, Fang-Chi %A Nho, Kwangsik %A Hofer, Edith %A Hagenaars, Saskia P %A Nyquist, Paul A %A Mishra, Aniket %A Adams, Hieab H H %A Li, Shuo %A Teumer, Alexander %A Zhao, Wei %A Freedman, Barry I %A Saba, Yasaman %A Yanek, Lisa R %A Chauhan, Ganesh %A van Buchem, Mark A %A Cushman, Mary %A Royle, Natalie A %A Bryan, R Nick %A Niessen, Wiro J %A Windham, Beverly G %A DeStefano, Anita L %A Habes, Mohamad %A Heckbert, Susan R %A Palmer, Nicholette D %A Lewis, Cora E %A Eiriksdottir, Gudny %A Maillard, Pauline %A Mathias, Rasika A %A Homuth, Georg %A Valdés-Hernández, Maria Del C %A Divers, Jasmin %A Beiser, Alexa S %A Langner, Sönke %A Rice, Kenneth M %A Bastin, Mark E %A Yang, Qiong %A Maldjian, Joseph A %A Starr, John M %A Sidney, Stephen %A Risacher, Shannon L %A Uitterlinden, André G %A Gudnason, Vilmundur G %A Nauck, Matthias %A Rotter, Jerome I %A Schreiner, Pamela J %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Mazoyer, Bernard %A von Sarnowski, Bettina %A Gottesman, Rebecca F %A Levy, Daniel %A Sigurdsson, Sigurdur %A Vernooij, Meike W %A Turner, Stephen T %A Schmidt, Reinhold %A Wardlaw, Joanna M %A Psaty, Bruce M %A Mosley, Thomas H %A DeCarli, Charles S %A Saykin, Andrew J %A Bowden, Donald W %A Becker, Diane M %A Deary, Ian J %A Schmidt, Helena %A Kardia, Sharon L R %A Ikram, M Arfan %A Debette, Stephanie %A Grabe, Hans J %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Fornage, Myriam %X

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

%B Stroke %8 2018 Jul 12 %G eng %R 10.1161/STROKEAHA.118.020689 %0 Journal Article %J Nat Genet %D 2018 %T Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. %A Evangelou, Evangelos %A Warren, Helen R %A Mosen-Ansorena, David %A Mifsud, Borbala %A Pazoki, Raha %A Gao, He %A Ntritsos, Georgios %A Dimou, Niki %A Cabrera, Claudia P %A Karaman, Ibrahim %A Ng, Fu Liang %A Evangelou, Marina %A Witkowska, Katarzyna %A Tzanis, Evan %A Hellwege, Jacklyn N %A Giri, Ayush %A Velez Edwards, Digna R %A Sun, Yan V %A Cho, Kelly %A Gaziano, J Michael %A Wilson, Peter W F %A Tsao, Philip S %A Kovesdy, Csaba P %A Esko, Tõnu %A Mägi, Reedik %A Milani, Lili %A Almgren, Peter %A Boutin, Thibaud %A Debette, Stephanie %A Ding, Jun %A Giulianini, Franco %A Holliday, Elizabeth G %A Jackson, Anne U %A Li-Gao, Ruifang %A Lin, Wei-Yu %A Luan, Jian'an %A Mangino, Massimo %A Oldmeadow, Christopher %A Prins, Bram Peter %A Qian, Yong %A Sargurupremraj, Muralidharan %A Shah, Nabi %A Surendran, Praveen %A Thériault, Sébastien %A Verweij, Niek %A Willems, Sara M %A Zhao, Jing-Hua %A Amouyel, Philippe %A Connell, John %A de Mutsert, Renée %A Doney, Alex S F %A Farrall, Martin %A Menni, Cristina %A Morris, Andrew D %A Noordam, Raymond %A Paré, Guillaume %A Poulter, Neil R %A Shields, Denis C %A Stanton, Alice %A Thom, Simon %A Abecasis, Goncalo %A Amin, Najaf %A Arking, Dan E %A Ayers, Kristin L %A Barbieri, Caterina M %A Batini, Chiara %A Bis, Joshua C %A Blake, Tineka %A Bochud, Murielle %A Boehnke, Michael %A Boerwinkle, Eric %A Boomsma, Dorret I %A Bottinger, Erwin P %A Braund, Peter S %A Brumat, Marco %A Campbell, Archie %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chauhan, Ganesh %A Ciullo, Marina %A Cocca, Massimiliano %A Collins, Francis %A Cordell, Heather J %A Davies, Gail %A Borst, Martin H de %A Geus, Eco J de %A Deary, Ian J %A Deelen, Joris %A del Greco M, Fabiola %A Demirkale, Cumhur Yusuf %A Dörr, Marcus %A Ehret, Georg B %A Elosua, Roberto %A Enroth, Stefan %A Erzurumluoglu, A Mesut %A Ferreira, Teresa %A Frånberg, Mattias %A Franco, Oscar H %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Gieger, Christian %A Girotto, Giorgia %A Goel, Anuj %A Gow, Alan J %A Gudnason, Vilmundur %A Guo, Xiuqing %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Harris, Sarah E %A Hartman, Catharina A %A Havulinna, Aki S %A Hicks, Andrew A %A Hofer, Edith %A Hofman, Albert %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Ingelsson, Erik %A James, Alan %A Jansen, Rick %A Jarvelin, Marjo-Riitta %A Joehanes, Roby %A Johansson, Asa %A Johnson, Andrew D %A Joshi, Peter K %A Jousilahti, Pekka %A Jukema, J Wouter %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Keavney, Bernard D %A Khaw, Kay-Tee %A Knekt, Paul %A Knight, Joanne %A Kolcic, Ivana %A Kooner, Jaspal S %A Koskinen, Seppo %A Kristiansson, Kati %A Kutalik, Zoltán %A Laan, Maris %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Lindgren, Cecilia M %A Liu, Yongmei %A Loos, Ruth J F %A Lopez, Lorna M %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Mamasoula, Chrysovalanto %A Marrugat, Jaume %A Marten, Jonathan %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew P %A Morrison, Alanna C %A Munson, Peter J %A Nalls, Mike A %A Nandakumar, Priyanka %A Nelson, Christopher P %A Niiranen, Teemu %A Nolte, Ilja M %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A O'Reilly, Paul F %A Org, Elin %A Padmanabhan, Sandosh %A Palmas, Walter %A Palotie, Aarno %A Pattie, Alison %A Penninx, Brenda W J H %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Pramstaller, Peter P %A Nguyen, Quang Tri %A Raitakari, Olli T %A Ren, Meixia %A Rettig, Rainer %A Rice, Kenneth %A Ridker, Paul M %A Ried, Janina S %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rose, Lynda M %A Rotter, Jerome I %A Rudan, Igor %A Ruggiero, Daniela %A Saba, Yasaman %A Sala, Cinzia F %A Salomaa, Veikko %A Samani, Nilesh J %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Schmidt, Helena %A Shrine, Nick %A Siscovick, David %A Smith, Albert V %A Snieder, Harold %A Sõber, Siim %A Sorice, Rossella %A Starr, John M %A Stott, David J %A Strachan, David P %A Strawbridge, Rona J %A Sundström, Johan %A Swertz, Morris A %A Taylor, Kent D %A Teumer, Alexander %A Tobin, Martin D %A Tomaszewski, Maciej %A Toniolo, Daniela %A Traglia, Michela %A Trompet, Stella %A Tuomilehto, Jaakko %A Tzourio, Christophe %A Uitterlinden, André G %A Vaez, Ahmad %A van der Most, Peter J %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Verwoert, Germaine C %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Vuckovic, Dragana %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Wright, Alan F %A Yao, Jie %A Zemunik, Tatijana %A Zhang, Weihua %A Attia, John R %A Butterworth, Adam S %A Chasman, Daniel I %A Conen, David %A Cucca, Francesco %A Danesh, John %A Hayward, Caroline %A Howson, Joanna M M %A Laakso, Markku %A Lakatta, Edward G %A Langenberg, Claudia %A Melander, Olle %A Mook-Kanamori, Dennis O %A Palmer, Colin N A %A Risch, Lorenz %A Scott, Robert A %A Scott, Rodney J %A Sever, Peter %A Spector, Tim D %A van der Harst, Pim %A Wareham, Nicholas J %A Zeggini, Eleftheria %A Levy, Daniel %A Munroe, Patricia B %A Newton-Cheh, Christopher %A Brown, Morris J %A Metspalu, Andres %A Hung, Adriana M %A O'Donnell, Christopher J %A Edwards, Todd L %A Psaty, Bruce M %A Tzoulaki, Ioanna %A Barnes, Michael R %A Wain, Louise V %A Elliott, Paul %A Caulfield, Mark J %X

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %R 10.1038/s41588-018-0205-x %0 Journal Article %J Nat Commun %D 2018 %T GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes. %A Franceschini, Nora %A Giambartolomei, Claudia %A de Vries, Paul S %A Finan, Chris %A Bis, Joshua C %A Huntley, Rachael P %A Lovering, Ruth C %A Tajuddin, Salman M %A Winkler, Thomas W %A Graff, Misa %A Kavousi, Maryam %A Dale, Caroline %A Smith, Albert V %A Hofer, Edith %A van Leeuwen, Elisabeth M %A Nolte, Ilja M %A Lu, Lingyi %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Pitkänen, Niina %A Franzén, Oscar %A Joshi, Peter K %A Noordam, Raymond %A Marioni, Riccardo E %A Hwang, Shih-Jen %A Musani, Solomon K %A Schminke, Ulf %A Palmas, Walter %A Isaacs, Aaron %A Correa, Adolfo %A Zonderman, Alan B %A Hofman, Albert %A Teumer, Alexander %A Cox, Amanda J %A Uitterlinden, André G %A Wong, Andrew %A Smit, Andries J %A Newman, Anne B %A Britton, Annie %A Ruusalepp, Arno %A Sennblad, Bengt %A Hedblad, Bo %A Pasaniuc, Bogdan %A Penninx, Brenda W %A Langefeld, Carl D %A Wassel, Christina L %A Tzourio, Christophe %A Fava, Cristiano %A Baldassarre, Damiano %A O'Leary, Daniel H %A Teupser, Daniel %A Kuh, Diana %A Tremoli, Elena %A Mannarino, Elmo %A Grossi, Enzo %A Boerwinkle, Eric %A Schadt, Eric E %A Ingelsson, Erik %A Veglia, Fabrizio %A Rivadeneira, Fernando %A Beutner, Frank %A Chauhan, Ganesh %A Heiss, Gerardo %A Snieder, Harold %A Campbell, Harry %A Völzke, Henry %A Markus, Hugh S %A Deary, Ian J %A Jukema, J Wouter %A de Graaf, Jacqueline %A Price, Jacqueline %A Pott, Janne %A Hopewell, Jemma C %A Liang, Jingjing %A Thiery, Joachim %A Engmann, Jorgen %A Gertow, Karl %A Rice, Kenneth %A Taylor, Kent D %A Dhana, Klodian %A Kiemeney, Lambertus A L M %A Lind, Lars %A Raffield, Laura M %A Launer, Lenore J %A Holdt, Lesca M %A Dörr, Marcus %A Dichgans, Martin %A Traylor, Matthew %A Sitzer, Matthias %A Kumari, Meena %A Kivimaki, Mika %A Nalls, Mike A %A Melander, Olle %A Raitakari, Olli %A Franco, Oscar H %A Rueda-Ochoa, Oscar L %A Roussos, Panos %A Whincup, Peter H %A Amouyel, Philippe %A Giral, Philippe %A Anugu, Pramod %A Wong, Quenna %A Malik, Rainer %A Rauramaa, Rainer %A Burkhardt, Ralph %A Hardy, Rebecca %A Schmidt, Reinhold %A de Mutsert, Renée %A Morris, Richard W %A Strawbridge, Rona J %A Wannamethee, S Goya %A Hägg, Sara %A Shah, Sonia %A McLachlan, Stela %A Trompet, Stella %A Seshadri, Sudha %A Kurl, Sudhir %A Heckbert, Susan R %A Ring, Susan %A Harris, Tamara B %A Lehtimäki, Terho %A Galesloot, Tessel E %A Shah, Tina %A de Faire, Ulf %A Plagnol, Vincent %A Rosamond, Wayne D %A Post, Wendy %A Zhu, Xiaofeng %A Zhang, Xiaoling %A Guo, Xiuqing %A Saba, Yasaman %A Dehghan, Abbas %A Seldenrijk, Adrie %A Morrison, Alanna C %A Hamsten, Anders %A Psaty, Bruce M %A van Duijn, Cornelia M %A Lawlor, Deborah A %A Mook-Kanamori, Dennis O %A Bowden, Donald W %A Schmidt, Helena %A Wilson, James F %A Wilson, James G %A Rotter, Jerome I %A Wardlaw, Joanna M %A Deanfield, John %A Halcox, Julian %A Lyytikäinen, Leo-Pekka %A Loeffler, Markus %A Evans, Michele K %A Debette, Stephanie %A Humphries, Steve E %A Völker, Uwe %A Gudnason, Vilmundur %A Hingorani, Aroon D %A Björkegren, Johan L M %A Casas, Juan P %A O'Donnell, Christopher J %K ADAMTS9 Protein %K Amino Acid Oxidoreductases %K Carotid Intima-Media Thickness %K Coronary Disease %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Lod Score %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %X

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

%B Nat Commun %V 9 %P 5141 %8 2018 12 03 %G eng %N 1 %R 10.1038/s41467-018-07340-5 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3 %0 Journal Article %J Brain %D 2019 %T Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. %A Mishra, Aniket %A Chauhan, Ganesh %A Violleau, Marie-Helene %A Vojinovic, Dina %A Jian, Xueqiu %A Bis, Joshua C %A Li, Shuo %A Saba, Yasaman %A Grenier-Boley, Benjamin %A Yang, Qiong %A Bartz, Traci M %A Hofer, Edith %A Soumaré, Aïcha %A Peng, Fen %A Duperron, Marie-Gabrielle %A Foglio, Mario %A Mosley, Thomas H %A Schmidt, Reinhold %A Psaty, Bruce M %A Launer, Lenore J %A Boerwinkle, Eric %A Zhu, Yicheng %A Mazoyer, Bernard %A Lathrop, Mark %A Bellenguez, Céline %A van Duijn, Cornelia M %A Ikram, M Arfan %A Schmidt, Helena %A Longstreth, W T %A Fornage, Myriam %A Seshadri, Sudha %A Joutel, Anne %A Tzourio, Christophe %A Debette, Stephanie %X

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

%B Brain %8 2019 Mar 11 %G eng %R 10.1093/brain/awz024 %0 Journal Article %J Nat Genet %D 2019 %T Genetic architecture of subcortical brain structures in 38,851 individuals. %A Satizabal, Claudia L %A Adams, Hieab H H %A Hibar, Derrek P %A White, Charles C %A Knol, Maria J %A Stein, Jason L %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Jahanshad, Neda %A Roshchupkin, Gennady V %A Smith, Albert V %A Bis, Joshua C %A Jian, Xueqiu %A Luciano, Michelle %A Hofer, Edith %A Teumer, Alexander %A van der Lee, Sven J %A Yang, Jingyun %A Yanek, Lisa R %A Lee, Tom V %A Li, Shuo %A Hu, Yanhui %A Koh, Jia Yu %A Eicher, John D %A Desrivières, Sylvane %A Arias-Vasquez, Alejandro %A Chauhan, Ganesh %A Athanasiu, Lavinia %A Rentería, Miguel E %A Kim, Sungeun %A Hoehn, David %A Armstrong, Nicola J %A Chen, Qiang %A Holmes, Avram J %A den Braber, Anouk %A Kloszewska, Iwona %A Andersson, Micael %A Espeseth, Thomas %A Grimm, Oliver %A Abramovic, Lucija %A Alhusaini, Saud %A Milaneschi, Yuri %A Papmeyer, Martina %A Axelsson, Tomas %A Ehrlich, Stefan %A Roiz-Santiañez, Roberto %A Kraemer, Bernd %A Håberg, Asta K %A Jones, Hannah J %A Pike, G Bruce %A Stein, Dan J %A Stevens, Allison %A Bralten, Janita %A Vernooij, Meike W %A Harris, Tamara B %A Filippi, Irina %A Witte, A Veronica %A Guadalupe, Tulio %A Wittfeld, Katharina %A Mosley, Thomas H %A Becker, James T %A Doan, Nhat Trung %A Hagenaars, Saskia P %A Saba, Yasaman %A Cuellar-Partida, Gabriel %A Amin, Najaf %A Hilal, Saima %A Nho, Kwangsik %A Mirza-Schreiber, Nazanin %A Arfanakis, Konstantinos %A Becker, Diane M %A Ames, David %A Goldman, Aaron L %A Lee, Phil H %A Boomsma, Dorret I %A Lovestone, Simon %A Giddaluru, Sudheer %A Le Hellard, Stephanie %A Mattheisen, Manuel %A Bohlken, Marc M %A Kasperaviciute, Dalia %A Schmaal, Lianne %A Lawrie, Stephen M %A Agartz, Ingrid %A Walton, Esther %A Tordesillas-Gutierrez, Diana %A Davies, Gareth E %A Shin, Jean %A Ipser, Jonathan C %A Vinke, Louis N %A Hoogman, Martine %A Jia, Tianye %A Burkhardt, Ralph %A Klein, Marieke %A Crivello, Fabrice %A Janowitz, Deborah %A Carmichael, Owen %A Haukvik, Unn K %A Aribisala, Benjamin S %A Schmidt, Helena %A Strike, Lachlan T %A Cheng, Ching-Yu %A Risacher, Shannon L %A Pütz, Benno %A Fleischman, Debra A %A Assareh, Amelia A %A Mattay, Venkata S %A Buckner, Randy L %A Mecocci, Patrizia %A Dale, Anders M %A Cichon, Sven %A Boks, Marco P %A Matarin, Mar %A Penninx, Brenda W J H %A Calhoun, Vince D %A Chakravarty, M Mallar %A Marquand, Andre F %A Macare, Christine %A Kharabian Masouleh, Shahrzad %A Oosterlaan, Jaap %A Amouyel, Philippe %A Hegenscheid, Katrin %A Rotter, Jerome I %A Schork, Andrew J %A Liewald, David C M %A de Zubicaray, Greig I %A Wong, Tien Yin %A Shen, Li %A Sämann, Philipp G %A Brodaty, Henry %A Roffman, Joshua L %A de Geus, Eco J C %A Tsolaki, Magda %A Erk, Susanne %A van Eijk, Kristel R %A Cavalleri, Gianpiero L %A van der Wee, Nic J A %A McIntosh, Andrew M %A Gollub, Randy L %A Bulayeva, Kazima B %A Bernard, Manon %A Richards, Jennifer S %A Himali, Jayandra J %A Loeffler, Markus %A Rommelse, Nanda %A Hoffmann, Wolfgang %A Westlye, Lars T %A Valdés Hernández, Maria C %A Hansell, Narelle K %A van Erp, Theo G M %A Wolf, Christiane %A Kwok, John B J %A Vellas, Bruno %A Heinz, Andreas %A Olde Loohuis, Loes M %A Delanty, Norman %A Ho, Beng-Choon %A Ching, Christopher R K %A Shumskaya, Elena %A Singh, Baljeet %A Hofman, Albert %A van der Meer, Dennis %A Homuth, Georg %A Psaty, Bruce M %A Bastin, Mark E %A Montgomery, Grant W %A Foroud, Tatiana M %A Reppermund, Simone %A Hottenga, Jouke-Jan %A Simmons, Andrew %A Meyer-Lindenberg, Andreas %A Cahn, Wiepke %A Whelan, Christopher D %A van Donkelaar, Marjolein M J %A Yang, Qiong %A Hosten, Norbert %A Green, Robert C %A Thalamuthu, Anbupalam %A Mohnke, Sebastian %A Hulshoff Pol, Hilleke E %A Lin, Honghuang %A Jack, Clifford R %A Schofield, Peter R %A Mühleisen, Thomas W %A Maillard, Pauline %A Potkin, Steven G %A Wen, Wei %A Fletcher, Evan %A Toga, Arthur W %A Gruber, Oliver %A Huentelman, Matthew %A Davey Smith, George %A Launer, Lenore J %A Nyberg, Lars %A Jönsson, Erik G %A Crespo-Facorro, Benedicto %A Koen, Nastassja %A Greve, Douglas N %A Uitterlinden, André G %A Weinberger, Daniel R %A Steen, Vidar M %A Fedko, Iryna O %A Groenewold, Nynke A %A Niessen, Wiro J %A Toro, Roberto %A Tzourio, Christophe %A Longstreth, William T %A Ikram, M Kamran %A Smoller, Jordan W %A van Tol, Marie-Jose %A Sussmann, Jessika E %A Paus, Tomáš %A Lemaître, Hervé %A Schroeter, Matthias L %A Mazoyer, Bernard %A Andreassen, Ole A %A Holsboer, Florian %A Depondt, Chantal %A Veltman, Dick J %A Turner, Jessica A %A Pausova, Zdenka %A Schumann, Gunter %A van Rooij, Daan %A Djurovic, Srdjan %A Deary, Ian J %A McMahon, Katie L %A Müller-Myhsok, Bertram %A Brouwer, Rachel M %A Soininen, Hilkka %A Pandolfo, Massimo %A Wassink, Thomas H %A Cheung, Joshua W %A Wolfers, Thomas %A Martinot, Jean-Luc %A Zwiers, Marcel P %A Nauck, Matthias %A Melle, Ingrid %A Martin, Nicholas G %A Kanai, Ryota %A Westman, Eric %A Kahn, René S %A Sisodiya, Sanjay M %A White, Tonya %A Saremi, Arvin %A van Bokhoven, Hans %A Brunner, Han G %A Völzke, Henry %A Wright, Margaret J %A van 't Ent, Dennis %A Nöthen, Markus M %A Ophoff, Roel A %A Buitelaar, Jan K %A Fernández, Guillén %A Sachdev, Perminder S %A Rietschel, Marcella %A van Haren, Neeltje E M %A Fisher, Simon E %A Beiser, Alexa S %A Francks, Clyde %A Saykin, Andrew J %A Mather, Karen A %A Romanczuk-Seiferth, Nina %A Hartman, Catharina A %A DeStefano, Anita L %A Heslenfeld, Dirk J %A Weiner, Michael W %A Walter, Henrik %A Hoekstra, Pieter J %A Nyquist, Paul A %A Franke, Barbara %A Bennett, David A %A Grabe, Hans J %A Johnson, Andrew D %A Chen, Christopher %A van Duijn, Cornelia M %A Lopez, Oscar L %A Fornage, Myriam %A Wardlaw, Joanna M %A Schmidt, Reinhold %A DeCarli, Charles %A De Jager, Philip L %A Villringer, Arno %A Debette, Stephanie %A Gudnason, Vilmundur %A Medland, Sarah E %A Shulman, Joshua M %A Thompson, Paul M %A Seshadri, Sudha %A Ikram, M Arfan %X

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

%B Nat Genet %V 51 %P 1624-1636 %8 2019 Nov %G eng %N 11 %R 10.1038/s41588-019-0511-y %0 Journal Article %J Nature %D 2022 %T Stroke genetics informs drug discovery and risk prediction across ancestries. %A Mishra, Aniket %A Malik, Rainer %A Hachiya, Tsuyoshi %A Jürgenson, Tuuli %A Namba, Shinichi %A Posner, Daniel C %A Kamanu, Frederick K %A Koido, Masaru %A Le Grand, Quentin %A Shi, Mingyang %A He, Yunye %A Georgakis, Marios K %A Caro, Ilana %A Krebs, Kristi %A Liaw, Yi-Ching %A Vaura, Felix C %A Lin, Kuang %A Winsvold, Bendik Slagsvold %A Srinivasasainagendra, Vinodh %A Parodi, Livia %A Bae, Hee-Joon %A Chauhan, Ganesh %A Chong, Michael R %A Tomppo, Liisa %A Akinyemi, Rufus %A Roshchupkin, Gennady V %A Habib, Naomi %A Jee, Yon Ho %A Thomassen, Jesper Qvist %A Abedi, Vida %A Cárcel-Márquez, Jara %A Nygaard, Marianne %A Leonard, Hampton L %A Yang, Chaojie %A Yonova-Doing, Ekaterina %A Knol, Maria J %A Lewis, Adam J %A Judy, Renae L %A Ago, Tetsuro %A Amouyel, Philippe %A Armstrong, Nicole D %A Bakker, Mark K %A Bartz, Traci M %A Bennett, David A %A Bis, Joshua C %A Bordes, Constance %A Børte, Sigrid %A Cain, Anael %A Ridker, Paul M %A Cho, Kelly %A Chen, Zhengming %A Cruchaga, Carlos %A Cole, John W %A De Jager, Phil L %A de Cid, Rafael %A Endres, Matthias %A Ferreira, Leslie E %A Geerlings, Mirjam I %A Gasca, Natalie C %A Gudnason, Vilmundur %A Hata, Jun %A He, Jing %A Heath, Alicia K %A Ho, Yuk-Lam %A Havulinna, Aki S %A Hopewell, Jemma C %A Hyacinth, Hyacinth I %A Inouye, Michael %A Jacob, Mina A %A Jeon, Christina E %A Jern, Christina %A Kamouchi, Masahiro %A Keene, Keith L %A Kitazono, Takanari %A Kittner, Steven J %A Konuma, Takahiro %A Kumar, Amit %A Lacaze, Paul %A Launer, Lenore J %A Lee, Keon-Joo %A Lepik, Kaido %A Li, Jiang %A Li, Liming %A Manichaikul, Ani %A Markus, Hugh S %A Marston, Nicholas A %A Meitinger, Thomas %A Mitchell, Braxton D %A Montellano, Felipe A %A Morisaki, Takayuki %A Mosley, Thomas H %A Nalls, Mike A %A Nordestgaard, Børge G %A O'Donnell, Martin J %A Okada, Yukinori %A Onland-Moret, N Charlotte %A Ovbiagele, Bruce %A Peters, Annette %A Psaty, Bruce M %A Rich, Stephen S %A Rosand, Jonathan %A Sabatine, Marc S %A Sacco, Ralph L %A Saleheen, Danish %A Sandset, Else Charlotte %A Salomaa, Veikko %A Sargurupremraj, Muralidharan %A Sasaki, Makoto %A Satizabal, Claudia L %A Schmidt, Carsten O %A Shimizu, Atsushi %A Smith, Nicholas L %A Sloane, Kelly L %A Sutoh, Yoichi %A Sun, Yan V %A Tanno, Kozo %A Tiedt, Steffen %A Tatlisumak, Turgut %A Torres-Aguila, Nuria P %A Tiwari, Hemant K %A Trégouët, David-Alexandre %A Trompet, Stella %A Tuladhar, Anil Man %A Tybjærg-Hansen, Anne %A van Vugt, Marion %A Vibo, Riina %A Verma, Shefali S %A Wiggins, Kerri L %A Wennberg, Patrik %A Woo, Daniel %A Wilson, Peter W F %A Xu, Huichun %A Yang, Qiong %A Yoon, Kyungheon %A Millwood, Iona Y %A Gieger, Christian %A Ninomiya, Toshiharu %A Grabe, Hans J %A Jukema, J Wouter %A Rissanen, Ina L %A Strbian, Daniel %A Kim, Young Jin %A Chen, Pei-Hsin %A Mayerhofer, Ernst %A Howson, Joanna M M %A Irvin, Marguerite R %A Adams, Hieab %A Wassertheil-Smoller, Sylvia %A Christensen, Kaare %A Ikram, Mohammad A %A Rundek, Tatjana %A Worrall, Bradford B %A Lathrop, G Mark %A Riaz, Moeen %A Simonsick, Eleanor M %A Kõrv, Janika %A França, Paulo H C %A Zand, Ramin %A Prasad, Kameshwar %A Frikke-Schmidt, Ruth %A de Leeuw, Frank-Erik %A Liman, Thomas %A Haeusler, Karl Georg %A Ruigrok, Ynte M %A Heuschmann, Peter Ulrich %A Longstreth, W T %A Jung, Keum Ji %A Bastarache, Lisa %A Paré, Guillaume %A Damrauer, Scott M %A Chasman, Daniel I %A Rotter, Jerome I %A Anderson, Christopher D %A Zwart, John-Anker %A Niiranen, Teemu J %A Fornage, Myriam %A Liaw, Yung-Po %A Seshadri, Sudha %A Fernandez-Cadenas, Israel %A Walters, Robin G %A Ruff, Christian T %A Owolabi, Mayowa O %A Huffman, Jennifer E %A Milani, Lili %A Kamatani, Yoichiro %A Dichgans, Martin %A Debette, Stephanie %X

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

%B Nature %8 2022 Sep 30 %G eng %R 10.1038/s41586-022-05165-3