@article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {8988, title = {Association of low-frequency and rare coding variants with information processing speed.}, journal = {Transl Psychiatry}, volume = {11}, year = {2021}, month = {2021 12 04}, pages = {613}, abstract = {

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67\%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 {\texttimes} 10) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

}, keywords = {Adult, Aging, Cognition, Genome-Wide Association Study, Geroscience, Humans, Polymorphism, Single Nucleotide, Ubiquitin-Protein Ligases}, issn = {2158-3188}, doi = {10.1038/s41398-021-01736-6}, author = {Bressler, Jan and Davies, Gail and Smith, Albert V and Saba, Yasaman and Bis, Joshua C and Jian, Xueqiu and Hayward, Caroline and Yanek, Lisa and Smith, Jennifer A and Mirza, Saira S and Wang, Ruiqi and Adams, Hieab H H and Becker, Diane and Boerwinkle, Eric and Campbell, Archie and Cox, Simon R and Eiriksdottir, Gudny and Fawns-Ritchie, Chloe and Gottesman, Rebecca F and Grove, Megan L and Guo, Xiuqing and Hofer, Edith and Kardia, Sharon L R and Knol, Maria J and Koini, Marisa and Lopez, Oscar L and Marioni, Riccardo E and Nyquist, Paul and Pattie, Alison and Polasek, Ozren and Porteous, David J and Rudan, Igor and Satizabal, Claudia L and Schmidt, Helena and Schmidt, Reinhold and Sidney, Stephen and Simino, Jeannette and Smith, Blair H and Turner, Stephen T and van der Lee, Sven J and Ware, Erin B and Whitmer, Rachel A and Yaffe, Kristine and Yang, Qiong and Zhao, Wei and Gudnason, Vilmundur and Launer, Lenore J and Fitzpatrick, Annette L and Psaty, Bruce M and Fornage, Myriam and Arfan Ikram, M and van Duijn, Cornelia M and Seshadri, Sudha and Mosley, Thomas H and Deary, Ian J} } @article {9184, title = {Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.}, journal = {Brain}, year = {2022}, month = {2022 Aug 09}, abstract = {

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at approximately 450,000 CpG sites in 9,732 middle-aged to older adults from 14 community-based studies. Single-CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single-CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 {\texttimes} 10-8), was associated with F2 expression in blood (P = 6.4 {\texttimes} 10-5), and colocalized with FOLH1 expression in brain (posterior probability =0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single-CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis, and multi-omics colocalization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug repositioning analysis indicated antihyperlipidemic agents, more specifically peroxisome proliferator-activated receptor alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood brain barrier disruption.

}, issn = {1460-2156}, doi = {10.1093/brain/awac290}, author = {Yang, Yunju and Knol, Maria J and Wang, Ruiqi and Mishra, Aniket and Liu, Dan and Luciano, Michelle and Teumer, Alexander and Armstrong, Nicola and Bis, Joshua C and Jhun, Min A and Li, Shuo and Adams, Hieab H H and Aziz, Nasir Ahmad and Bastin, Mark E and Bourgey, Mathieu and Brody, Jennifer A and Frenzel, Stefan and Gottesman, Rebecca F and Hosten, Norbert and Hou, Lifang and Kardia, Sharon L R and Lohner, Valerie and Marquis, Pascale and Maniega, Susana Mu{\~n}oz and Satizabal, Claudia L and Sorond, Farzaneh A and Vald{\'e}s Hern{\'a}ndez, Maria C and van Duijn, Cornelia M and Vernooij, Meike W and Wittfeld, Katharina and Yang, Qiong and Zhao, Wei and Boerwinkle, Eric and Levy, Daniel and Deary, Ian J and Jiang, Jiyang and Mather, Karen A and Mosley, Thomas H and Psaty, Bruce M and Sachdev, Perminder S and Smith, Jennifer A and Sotoodehnia, Nona and DeCarli, Charles S and Breteler, Monique M B and Arfan Ikram, M and Grabe, Hans J and Wardlaw, Joanna and Longstreth, W T and Launer, Lenore J and Seshadri, Sudha and Debette, Stephanie and Fornage, Myriam} } @article {9169, title = {Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning.}, journal = {Mol Psychiatry}, year = {2022}, month = {2022 Aug 16}, abstract = {

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

}, issn = {1476-5578}, doi = {10.1038/s41380-022-01710-8}, author = {Lahti, Jari and Tuominen, Samuli and Yang, Qiong and Pergola, Giulio and Ahmad, Shahzad and Amin, Najaf and Armstrong, Nicola J and Beiser, Alexa and Bey, Katharina and Bis, Joshua C and Boerwinkle, Eric and Bressler, Jan and Campbell, Archie and Campbell, Harry and Chen, Qiang and Corley, Janie and Cox, Simon R and Davies, Gail and De Jager, Philip L and Derks, Eske M and Faul, Jessica D and Fitzpatrick, Annette L and Fohner, Alison E and Ford, Ian and Fornage, Myriam and Gerring, Zachary and Grabe, Hans J and Grodstein, Francine and Gudnason, Vilmundur and Simonsick, Eleanor and Holliday, Elizabeth G and Joshi, Peter K and Kajantie, Eero and Kaprio, Jaakko and Karell, Pauliina and Kleineidam, Luca and Knol, Maria J and Kochan, Nicole A and Kwok, John B and Leber, Markus and Lam, Max and Lee, Teresa and Li, Shuo and Loukola, Anu and Luck, Tobias and Marioni, Riccardo E and Mather, Karen A and Medland, Sarah and Mirza, Saira S and Nalls, Mike A and Nho, Kwangsik and O{\textquoteright}Donnell, Adrienne and Oldmeadow, Christopher and Painter, Jodie and Pattie, Alison and Reppermund, Simone and Risacher, Shannon L and Rose, Richard J and Sadashivaiah, Vijay and Scholz, Markus and Satizabal, Claudia L and Schofield, Peter W and Schraut, Katharina E and Scott, Rodney J and Simino, Jeannette and Smith, Albert V and Smith, Jennifer A and Stott, David J and Surakka, Ida and Teumer, Alexander and Thalamuthu, Anbupalam and Trompet, Stella and Turner, Stephen T and van der Lee, Sven J and Villringer, Arno and V{\"o}lker, Uwe and Wilson, Robert S and Wittfeld, Katharina and Vuoksimaa, Eero and Xia, Rui and Yaffe, Kristine and Yu, Lei and Zare, Habil and Zhao, Wei and Ames, David and Attia, John and Bennett, David A and Brodaty, Henry and Chasman, Daniel I and Goldman, Aaron L and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon L R and Lencz, Todd and Loeffler, Markus and Mattay, Venkata S and Palotie, Aarno and Psaty, Bruce M and Ramirez, Alfredo and Ridker, Paul M and Riedel-Heller, Steffi G and Sachdev, Perminder S and Saykin, Andrew J and Scherer, Martin and Schofield, Peter R and Sidney, Stephen and Starr, John M and Trollor, Julian and Ulrich, William and Wagner, Michael and Weir, David R and Wilson, James F and Wright, Margaret J and Weinberger, Daniel R and Debette, Stephanie and Eriksson, Johan G and Mosley, Thomas H and Launer, Lenore J and van Duijn, Cornelia M and Deary, Ian J and Seshadri, Sudha and R{\"a}ikk{\"o}nen, Katri} } @article {9172, title = {Stroke genetics informs drug discovery and risk prediction across ancestries.}, journal = {Nature}, year = {2022}, month = {2022 Sep 30}, abstract = {

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.

}, issn = {1476-4687}, doi = {10.1038/s41586-022-05165-3}, author = {Mishra, Aniket and Malik, Rainer and Hachiya, Tsuyoshi and J{\"u}rgenson, Tuuli and Namba, Shinichi and Posner, Daniel C and Kamanu, Frederick K and Koido, Masaru and Le Grand, Quentin and Shi, Mingyang and He, Yunye and Georgakis, Marios K and Caro, Ilana and Krebs, Kristi and Liaw, Yi-Ching and Vaura, Felix C and Lin, Kuang and Winsvold, Bendik Slagsvold and Srinivasasainagendra, Vinodh and Parodi, Livia and Bae, Hee-Joon and Chauhan, Ganesh and Chong, Michael R and Tomppo, Liisa and Akinyemi, Rufus and Roshchupkin, Gennady V and Habib, Naomi and Jee, Yon Ho and Thomassen, Jesper Qvist and Abedi, Vida and C{\'a}rcel-M{\'a}rquez, Jara and Nygaard, Marianne and Leonard, Hampton L and Yang, Chaojie and Yonova-Doing, Ekaterina and Knol, Maria J and Lewis, Adam J and Judy, Renae L and Ago, Tetsuro and Amouyel, Philippe and Armstrong, Nicole D and Bakker, Mark K and Bartz, Traci M and Bennett, David A and Bis, Joshua C and Bordes, Constance and B{\o}rte, Sigrid and Cain, Anael and Ridker, Paul M and Cho, Kelly and Chen, Zhengming and Cruchaga, Carlos and Cole, John W and De Jager, Phil L and de Cid, Rafael and Endres, Matthias and Ferreira, Leslie E and Geerlings, Mirjam I and Gasca, Natalie C and Gudnason, Vilmundur and Hata, Jun and He, Jing and Heath, Alicia K and Ho, Yuk-Lam and Havulinna, Aki S and Hopewell, Jemma C and Hyacinth, Hyacinth I and Inouye, Michael and Jacob, Mina A and Jeon, Christina E and Jern, Christina and Kamouchi, Masahiro and Keene, Keith L and Kitazono, Takanari and Kittner, Steven J and Konuma, Takahiro and Kumar, Amit and Lacaze, Paul and Launer, Lenore J and Lee, Keon-Joo and Lepik, Kaido and Li, Jiang and Li, Liming and Manichaikul, Ani and Markus, Hugh S and Marston, Nicholas A and Meitinger, Thomas and Mitchell, Braxton D and Montellano, Felipe A and Morisaki, Takayuki and Mosley, Thomas H and Nalls, Mike A and Nordestgaard, B{\o}rge G and O{\textquoteright}Donnell, Martin J and Okada, Yukinori and Onland-Moret, N Charlotte and Ovbiagele, Bruce and Peters, Annette and Psaty, Bruce M and Rich, Stephen S and Rosand, Jonathan and Sabatine, Marc S and Sacco, Ralph L and Saleheen, Danish and Sandset, Else Charlotte and Salomaa, Veikko and Sargurupremraj, Muralidharan and Sasaki, Makoto and Satizabal, Claudia L and Schmidt, Carsten O and Shimizu, Atsushi and Smith, Nicholas L and Sloane, Kelly L and Sutoh, Yoichi and Sun, Yan V and Tanno, Kozo and Tiedt, Steffen and Tatlisumak, Turgut and Torres-Aguila, Nuria P and Tiwari, Hemant K and Tr{\'e}gou{\"e}t, David-Alexandre and Trompet, Stella and Tuladhar, Anil Man and Tybj{\ae}rg-Hansen, Anne and van Vugt, Marion and Vibo, Riina and Verma, Shefali S and Wiggins, Kerri L and Wennberg, Patrik and Woo, Daniel and Wilson, Peter W F and Xu, Huichun and Yang, Qiong and Yoon, Kyungheon and Millwood, Iona Y and Gieger, Christian and Ninomiya, Toshiharu and Grabe, Hans J and Jukema, J Wouter and Rissanen, Ina L and Strbian, Daniel and Kim, Young Jin and Chen, Pei-Hsin and Mayerhofer, Ernst and Howson, Joanna M M and Irvin, Marguerite R and Adams, Hieab and Wassertheil-Smoller, Sylvia and Christensen, Kaare and Ikram, Mohammad A and Rundek, Tatjana and Worrall, Bradford B and Lathrop, G Mark and Riaz, Moeen and Simonsick, Eleanor M and K{\~o}rv, Janika and Fran{\c c}a, Paulo H C and Zand, Ramin and Prasad, Kameshwar and Frikke-Schmidt, Ruth and de Leeuw, Frank-Erik and Liman, Thomas and Haeusler, Karl Georg and Ruigrok, Ynte M and Heuschmann, Peter Ulrich and Longstreth, W T and Jung, Keum Ji and Bastarache, Lisa and Par{\'e}, Guillaume and Damrauer, Scott M and Chasman, Daniel I and Rotter, Jerome I and Anderson, Christopher D and Zwart, John-Anker and Niiranen, Teemu J and Fornage, Myriam and Liaw, Yung-Po and Seshadri, Sudha and Fernandez-Cadenas, Israel and Walters, Robin G and Ruff, Christian T and Owolabi, Mayowa O and Huffman, Jennifer E and Milani, Lili and Kamatani, Yoichiro and Dichgans, Martin and Debette, Stephanie} } @article {9505, title = {Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 13}, abstract = {

IMPORTANCE: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.

OBJECTIVE: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.

DESIGN SETTING AND PARTICIPANTS: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.

MAIN OUTCOMES AND MEASURES: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (AD , n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.

RESULTS: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of AD (OR, 1.16; 95\%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95\%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and AD , with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95\%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.

CONCLUSION: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

KEY POINTS: Do instrumental variable analyses leveraging genetic information provide evidence for a causal association of various vascular traits with Alzheimer{\textquoteright}s disease (AD) and all-cause-dementia? How do these associations compare for white matter hyperintensity (WMH) burden, a highly prevalent marker of covert cerebral small vessel disease (cSVD), stroke, and blood pressure traits, the strongest known risk factor for cSVD and stroke? Using Mendelian randomization (MR) leveraging large, published genome-wide association studies, this study showed a putative causal association of larger WMH burden with increased AD risk after accounting for pulse pressure effects, and some evidence for association of lower BP with AD risk with possible confounding by shared genetic instruments. Longitudinal analyses on individual-level data also supported association of genetically determined WMH with incident all-cause-dementia and AD, independently of interim stroke. This study using complementary genetic epidemiology approaches, identified increasing WMH burden to be associated with dementia and AD risk, suggesting the association as specific for cSVD and independent of BP and stroke.

}, doi = {10.1101/2023.08.08.23293761}, author = {Sargurupremraj, Muralidharan and Soumar{\'e}, A{\"\i}cha and Bis, Joshua C and Surakka, Ida and J{\"u}rgenson, Tuuli and Joly, Pierre and Knol, Maria J and Wang, Ruiqi and Yang, Qiong and Satizabal, Claudia L and Gudjonsson, Alexander and Mishra, Aniket and Bouteloup, Vincent and Phuah, Chia-Ling and van Duijn, Cornelia M and Cruchaga, Carlos and Dufouil, Carole and Chene, Genevi{\`e}ve and Lopez, Oscar and Psaty, Bruce M and Tzourio, Christophe and Amouyel, Philippe and Adams, Hieab H and Jacqmin-Gadda, H{\'e}l{\`e}ne and Ikram, Mohammad Arfan and Gudnason, Vilmundur and Milani, Lili and Winsvold, Bendik S and Hveem, Kristian and Matthews, Paul M and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Debette, Stephanie} } @article {9706, title = {Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.}, journal = {JAMA Netw Open}, volume = {7}, year = {2024}, month = {2024 May 01}, pages = {e2412824}, abstract = {

IMPORTANCE: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain.

OBJECTIVE: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases.

DESIGN, SETTING, AND PARTICIPANTS: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022.

EXPOSURES: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations.

MAIN OUTCOMES AND MEASURES: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses.

RESULTS: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9\% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95\% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95\% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4\% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95\% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95\% CI, 1.03-1.06; P = 1.9 {\texttimes} 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke.

CONCLUSIONS: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Blood Pressure, Cerebral Small Vessel Diseases, Dementia, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mendelian Randomization Analysis, Prospective Studies, Risk Factors, Stroke}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2024.12824}, author = {Sargurupremraj, Muralidharan and Soumar{\'e}, A{\"\i}cha and Bis, Joshua C and Surakka, Ida and J{\"u}rgenson, Tuuli and Joly, Pierre and Knol, Maria J and Wang, Ruiqi and Yang, Qiong and Satizabal, Claudia L and Gudjonsson, Alexander and Mishra, Aniket and Bouteloup, Vincent and Phuah, Chia-Ling and van Duijn, Cornelia M and Cruchaga, Carlos and Dufouil, Carole and Chene, Genevi{\`e}ve and Lopez, Oscar L and Psaty, Bruce M and Tzourio, Christophe and Amouyel, Philippe and Adams, Hieab H and Jacqmin-Gadda, H{\'e}l{\`e}ne and Ikram, Mohammad Arfan and Gudnason, Vilmundur and Milani, Lili and Winsvold, Bendik S and Hveem, Kristian and Matthews, Paul M and Longstreth, W T and Seshadri, Sudha and Launer, Lenore J and Debette, Stephanie} }