@article {6578, title = {Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {335-43}, abstract = {

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with >=1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency >=1\%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Research Design, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000350}, author = {Lin, Honghuang and Wang, Min and Brody, Jennifer A and Bis, Joshua C and Dupuis, Jos{\'e}e and Lumley, Thomas and McKnight, Barbara and Rice, Kenneth M and Sitlani, Colleen M and Reid, Jeffrey G and Bressler, Jan and Liu, Xiaoming and Davis, Brian C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Kovar, Christie L and Dinh, Huyen and Wu, Yuanqing and Newsham, Irene and Chen, Han and Broka, Andi and DeStefano, Anita L and Gupta, Mayetri and Lunetta, Kathryn L and Liu, Ching-Ti and White, Charles C and Xing, Chuanhua and Zhou, Yanhua and Benjamin, Emelia J and Schnabel, Renate B and Heckbert, Susan R and Psaty, Bruce M and Muzny, Donna M and Cupples, L Adrienne and Morrison, Alanna C and Boerwinkle, Eric} } @article {6684, title = {Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Biol Psychiatry}, volume = {77}, year = {2015}, month = {2015 Apr 15}, pages = {749-63}, abstract = {

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 {\texttimes} 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 {\texttimes} 10(-10)) and replication cohorts (p = 5.65 {\texttimes} 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 {\texttimes} 10(-8), and rs6813517 [SPOCK3], p = 2.58 {\texttimes} 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.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoproteins E, Claudin-5, Cohort Studies, Female, Genome-Wide Association Study, Genotype, Humans, Male, Memory Disorders, Middle Aged, Polymorphism, Single Nucleotide, Proteins, Proteoglycans, Regression Analysis, Sulfotransferases, Verbal Learning}, issn = {1873-2402}, doi = {10.1016/j.biopsych.2014.08.027}, author = {Debette, Stephanie and Ibrahim Verbaas, Carla A and Bressler, Jan and Schuur, Maaike and Smith, Albert and Bis, Joshua C and Davies, Gail and Wolf, Christiane and Gudnason, Vilmundur and Chibnik, Lori B and Yang, Qiong and DeStefano, Anita L and de Quervain, Dominique J F and Srikanth, Velandai and Lahti, Jari and Grabe, Hans J and Smith, Jennifer A and Priebe, Lutz and Yu, Lei and Karbalai, Nazanin and Hayward, Caroline and Wilson, James F and Campbell, Harry and Petrovic, Katja and Fornage, Myriam and Chauhan, Ganesh and Yeo, Robin and Boxall, Ruth and Becker, James and Stegle, Oliver and Mather, Karen A and Chouraki, Vincent and Sun, Qi and Rose, Lynda M and Resnick, Susan and Oldmeadow, Christopher and Kirin, Mirna and Wright, Alan F and Jonsdottir, Maria K and Au, Rhoda and Becker, Albert and Amin, Najaf and Nalls, Mike A and Turner, Stephen T and Kardia, Sharon L R and Oostra, Ben and Windham, Gwen and Coker, Laura H and Zhao, Wei and Knopman, David S and Heiss, Gerardo and Griswold, Michael E and Gottesman, Rebecca F and Vitart, Veronique and Hastie, Nicholas D and Zgaga, Lina and Rudan, Igor and Polasek, Ozren and Holliday, Elizabeth G and Schofield, Peter and Choi, Seung Hoan and Tanaka, Toshiko and An, Yang and Perry, Rodney T and Kennedy, Richard E and Sale, Mich{\`e}le M and Wang, Jing and Wadley, Virginia G and Liewald, David C and Ridker, Paul M and Gow, Alan J and Pattie, Alison and Starr, John M and Porteous, David and Liu, Xuan and Thomson, Russell and Armstrong, Nicola J and Eiriksdottir, Gudny and Assareh, Arezoo A and Kochan, Nicole A and Widen, Elisabeth and Palotie, Aarno and Hsieh, Yi-Chen and Eriksson, Johan G and Vogler, Christian and van Swieten, John C and Shulman, Joshua M and Beiser, Alexa and Rotter, Jerome and Schmidt, Carsten O and Hoffmann, Wolfgang and N{\"o}then, Markus M and Ferrucci, Luigi and Attia, John and Uitterlinden, Andr{\'e} G and Amouyel, Philippe and Dartigues, Jean-Fran{\c c}ois and Amieva, H{\'e}l{\`e}ne and R{\"a}ikk{\"o}nen, Katri and Garcia, Melissa and Wolf, Philip A and Hofman, Albert and Longstreth, W T and Psaty, Bruce M and Boerwinkle, Eric and DeJager, Philip L and Sachdev, Perminder S and Schmidt, Reinhold and Breteler, Monique M B and Teumer, Alexander and Lopez, Oscar L and Cichon, Sven and Chasman, Daniel I and Grodstein, Francine and M{\"u}ller-Myhsok, Bertram and Tzourio, Christophe and Papassotiropoulos, Andreas and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Mosley, Thomas H} } @article {7349, title = {DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases.}, journal = {Genome Biol}, volume = {17}, year = {2016}, month = {2016 Dec 12}, pages = {255}, abstract = {

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

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

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

}, issn = {1474-760X}, doi = {10.1186/s13059-016-1119-5}, author = {Ligthart, Symen and Marzi, Carola and Aslibekyan, Stella and Mendelson, Michael M and Conneely, Karen N and Tanaka, Toshiko and Colicino, Elena and Waite, Lindsay L and Joehanes, Roby and Guan, Weihua and Brody, Jennifer A and Elks, Cathy and Marioni, Riccardo and Jhun, Min A and Agha, Golareh and Bressler, Jan and Ward-Caviness, Cavin K and Chen, Brian H and Huan, Tianxiao and Bakulski, Kelly and Salfati, Elias L and Fiorito, Giovanni and Wahl, Simone and Schramm, Katharina and Sha, Jin and Hernandez, Dena G and Just, Allan C and Smith, Jennifer A and Sotoodehnia, Nona and Pilling, Luke C and Pankow, James S and Tsao, Phil S and Liu, Chunyu and Zhao, Wei and Guarrera, Simonetta and Michopoulos, Vasiliki J and Smith, Alicia K and Peters, Marjolein J and Melzer, David and Vokonas, Pantel and Fornage, Myriam and Prokisch, Holger and Bis, Joshua C and Chu, Audrey Y and Herder, Christian and Grallert, Harald and Yao, Chen and Shah, Sonia and McRae, Allan F and Lin, Honghuang and Horvath, Steve and Fallin, Daniele and Hofman, Albert and Wareham, Nicholas J and Wiggins, Kerri L and Feinberg, Andrew P and Starr, John M and Visscher, Peter M and Murabito, Joanne M and Kardia, Sharon L R and Absher, Devin M and Binder, Elisabeth B and Singleton, Andrew B and Bandinelli, Stefania and Peters, Annette and Waldenberger, Melanie and Matullo, Giuseppe and Schwartz, Joel D and Demerath, Ellen W and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B J and Franco, Oscar H and Chen, Yii-Der Ida and Levy, Daniel and Turner, Stephen T and Deary, Ian J and Ressler, Kerry J and Dupuis, Jos{\'e}e and Ferrucci, Luigi and Ong, Ken K and Assimes, Themistocles L and Boerwinkle, Eric and Koenig, Wolfgang and Arnett, Donna K and Baccarelli, Andrea A and Benjamin, Emelia J and Dehghan, Abbas} } @article {7261, title = {Epigenetic Signatures of Cigarette Smoking.}, journal = {Circ Cardiovasc Genet}, volume = {9}, year = {2016}, month = {2016 Oct}, pages = {436-447}, abstract = {

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

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

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

}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001506}, author = {Joehanes, Roby and Just, Allan C and Marioni, Riccardo E and Pilling, Luke C and Reynolds, Lindsay M and Mandaviya, Pooja R and Guan, Weihua and Xu, Tao and Elks, Cathy E and Aslibekyan, Stella and Moreno-Macias, Hortensia and Smith, Jennifer A and Brody, Jennifer A and Dhingra, Radhika and Yousefi, Paul and Pankow, James S and Kunze, Sonja and Shah, Sonia H and McRae, Allan F and Lohman, Kurt and Sha, Jin and Absher, Devin M and Ferrucci, Luigi and Zhao, Wei and Demerath, Ellen W and Bressler, Jan and Grove, Megan L and Huan, Tianxiao and Liu, Chunyu and Mendelson, Michael M and Yao, Chen and Kiel, Douglas P and Peters, Annette and Wang-Sattler, Rui and Visscher, Peter M and Wray, Naomi R and Starr, John M and Ding, Jingzhong and Rodriguez, Carlos J and Wareham, Nicholas J and Irvin, Marguerite R and Zhi, Degui and Barrdahl, Myrto and Vineis, Paolo and Ambatipudi, Srikant and Uitterlinden, Andr{\'e} G and Hofman, Albert and Schwartz, Joel and Colicino, Elena and Hou, Lifang and Vokonas, Pantel S and Hernandez, Dena G and Singleton, Andrew B and Bandinelli, Stefania and Turner, Stephen T and Ware, Erin B and Smith, Alicia K and Klengel, Torsten and Binder, Elisabeth B and Psaty, Bruce M and Taylor, Kent D and Gharib, Sina A and Swenson, Brenton R and Liang, Liming and DeMeo, Dawn L and O{\textquoteright}Connor, George T and Herceg, Zdenko and Ressler, Kerry J and Conneely, Karen N and Sotoodehnia, Nona and Kardia, Sharon L R and Melzer, David and Baccarelli, Andrea A and van Meurs, Joyce B J and Romieu, Isabelle and Arnett, Donna K and Ong, Ken K and Liu, Yongmei and Waldenberger, Melanie and Deary, Ian J and Fornage, Myriam and Levy, Daniel and London, Stephanie J} } @article {7583, title = {DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Dec 07}, pages = {888-902}, abstract = {

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

}, keywords = {Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.028}, author = {Richard, Melissa A and Huan, Tianxiao and Ligthart, Symen and Gondalia, Rahul and Jhun, Min A and Brody, Jennifer A and Irvin, Marguerite R and Marioni, Riccardo and Shen, Jincheng and Tsai, Pei-Chien and Montasser, May E and Jia, Yucheng and Syme, Catriona and Salfati, Elias L and Boerwinkle, Eric and Guan, Weihua and Mosley, Thomas H and Bressler, Jan and Morrison, Alanna C and Liu, Chunyu and Mendelson, Michael M and Uitterlinden, Andr{\'e} G and van Meurs, Joyce B and Franco, Oscar H and Zhang, Guosheng and Li, Yun and Stewart, James D and Bis, Joshua C and Psaty, Bruce M and Chen, Yii-Der Ida and Kardia, Sharon L R and Zhao, Wei and Turner, Stephen T and Absher, Devin and Aslibekyan, Stella and Starr, John M and McRae, Allan F and Hou, Lifang and Just, Allan C and Schwartz, Joel D and Vokonas, Pantel S and Menni, Cristina and Spector, Tim D and Shuldiner, Alan and Damcott, Coleen M and Rotter, Jerome I and Palmas, Walter and Liu, Yongmei and Paus, Tom{\'a}{\v s} and Horvath, Steve and O{\textquoteright}Connell, Jeffrey R and Guo, Xiuqing and Pausova, Zdenka and Assimes, Themistocles L and Sotoodehnia, Nona and Smith, Jennifer A and Arnett, Donna K and Deary, Ian J and Baccarelli, Andrea A and Bell, Jordana T and Whitsel, Eric and Dehghan, Abbas and Levy, Daniel and Fornage, Myriam} } @article {7788, title = {Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 May 29}, pages = {2098}, abstract = {

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 {\texttimes} 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3\% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-04362-x}, author = {Davies, Gail and Lam, Max and Harris, Sarah E and Trampush, Joey W and Luciano, Michelle and Hill, W David and Hagenaars, Saskia P and Ritchie, Stuart J and Marioni, Riccardo E and Fawns-Ritchie, Chloe and Liewald, David C M and Okely, Judith A and Ahola-Olli, Ari V and Barnes, Catriona L K and Bertram, Lars and Bis, Joshua C and Burdick, Katherine E and Christoforou, Andrea and DeRosse, Pamela and Djurovic, Srdjan and Espeseth, Thomas and Giakoumaki, Stella and Giddaluru, Sudheer and Gustavson, Daniel E and Hayward, Caroline and Hofer, Edith and Ikram, M Arfan and Karlsson, Robert and Knowles, Emma and Lahti, Jari and Leber, Markus and Li, Shuo and Mather, Karen A and Melle, Ingrid and Morris, Derek and Oldmeadow, Christopher and Palviainen, Teemu and Payton, Antony and Pazoki, Raha and Petrovic, Katja and Reynolds, Chandra A and Sargurupremraj, Muralidharan and Scholz, Markus and Smith, Jennifer A and Smith, Albert V and Terzikhan, Natalie and Thalamuthu, Anbupalam and Trompet, Stella and van der Lee, Sven J and Ware, Erin B and Windham, B Gwen and Wright, Margaret J and Yang, Jingyun and Yu, Jin and Ames, David and Amin, Najaf and Amouyel, Philippe and Andreassen, Ole A and Armstrong, Nicola J and Assareh, Amelia A and Attia, John R and Attix, Deborah and Avramopoulos, Dimitrios and Bennett, David A and B{\"o}hmer, Anne C and Boyle, Patricia A and Brodaty, Henry and Campbell, Harry and Cannon, Tyrone D and Cirulli, Elizabeth T and Congdon, Eliza and Conley, Emily Drabant and Corley, Janie and Cox, Simon R and Dale, Anders M and Dehghan, Abbas and Dick, Danielle and Dickinson, Dwight and Eriksson, Johan G and Evangelou, Evangelos and Faul, Jessica D and Ford, Ian and Freimer, Nelson A and Gao, He and Giegling, Ina and Gillespie, Nathan A and Gordon, Scott D and Gottesman, Rebecca F and Griswold, Michael E and Gudnason, Vilmundur and Harris, Tamara B and Hartmann, Annette M and Hatzimanolis, Alex and Heiss, Gerardo and Holliday, Elizabeth G and Joshi, Peter K and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and Karlsson, Ida and Kleineidam, Luca and Knopman, David S and Kochan, Nicole A and Konte, Bettina and Kwok, John B and Le Hellard, Stephanie and Lee, Teresa and Lehtim{\"a}ki, Terho and Li, Shu-Chen and Liu, Tian and Koini, Marisa and London, Edythe and Longstreth, Will T and Lopez, Oscar L and Loukola, Anu and Luck, Tobias and Lundervold, Astri J and Lundquist, Anders and Lyytik{\"a}inen, Leo-Pekka and Martin, Nicholas G and Montgomery, Grant W and Murray, Alison D and Need, Anna C and Noordam, Raymond and Nyberg, Lars and Ollier, William and Papenberg, Goran and Pattie, Alison and Polasek, Ozren and Poldrack, Russell A and Psaty, Bruce M and Reppermund, Simone and Riedel-Heller, Steffi G and Rose, Richard J and Rotter, Jerome I and Roussos, Panos and Rovio, Suvi P and Saba, Yasaman and Sabb, Fred W and Sachdev, Perminder S and Satizabal, Claudia L and Schmid, Matthias and Scott, Rodney J and Scult, Matthew A and Simino, Jeannette and Slagboom, P Eline and Smyrnis, Nikolaos and Soumar{\'e}, A{\"\i}cha and Stefanis, Nikos C and Stott, David J and Straub, Richard E and Sundet, Kjetil and Taylor, Adele M and Taylor, Kent D and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andre and Vitart, Veronique and Voineskos, Aristotle N and Kaprio, Jaakko and Wagner, Michael and Wagner, Holger and Weinhold, Leonie and Wen, K Hoyan and Widen, Elisabeth and Yang, Qiong and Zhao, Wei and Adams, Hieab H H and Arking, Dan E and Bilder, Robert M and Bitsios, Panos and Boerwinkle, Eric and Chiba-Falek, Ornit and Corvin, Aiden and De Jager, Philip L and Debette, Stephanie and Donohoe, Gary and Elliott, Paul and Fitzpatrick, Annette L and Gill, Michael and Glahn, David C and H{\"a}gg, Sara and Hansell, Narelle K and Hariri, Ahmad R and Ikram, M Kamran and Jukema, J Wouter and Vuoksimaa, Eero and Keller, Matthew C and Kremen, William S and Launer, Lenore and Lindenberger, Ulman and Palotie, Aarno and Pedersen, Nancy L and Pendleton, Neil and Porteous, David J and R{\"a}ikk{\"o}nen, Katri and Raitakari, Olli T and Ramirez, Alfredo and Reinvang, Ivar and Rudan, Igor and Schmidt, Reinhold and Schmidt, Helena and Schofield, Peter W and Schofield, Peter R and Starr, John M and Steen, Vidar M and Trollor, Julian N and Turner, Steven T and van Duijn, Cornelia M and Villringer, Arno and Weinberger, Daniel R and Weir, David R and Wilson, James F and Malhotra, Anil and McIntosh, Andrew M and Gale, Catharine R and Seshadri, Sudha and Mosley, Thomas H and Bressler, Jan and Lencz, Todd and Deary, Ian J} } @article {8507, title = {Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.}, journal = {Circulation}, volume = {140}, year = {2019}, month = {2019 08 20}, pages = {645-657}, abstract = {

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67\% women, 35\% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.039357}, author = {Agha, Golareh and Mendelson, Michael M and Ward-Caviness, Cavin K and Joehanes, Roby and Huan, Tianxiao and Gondalia, Rahul and Salfati, Elias and Brody, Jennifer A and Fiorito, Giovanni and Bressler, Jan and Chen, Brian H and Ligthart, Symen and Guarrera, Simonetta and Colicino, Elena and Just, Allan C and Wahl, Simone and Gieger, Christian and Vandiver, Amy R and Tanaka, Toshiko and Hernandez, Dena G and Pilling, Luke C and Singleton, Andrew B and Sacerdote, Carlotta and Krogh, Vittorio and Panico, Salvatore and Tumino, Rosario and Li, Yun and Zhang, Guosheng and Stewart, James D and Floyd, James S and Wiggins, Kerri L and Rotter, Jerome I and Multhaup, Michael and Bakulski, Kelly and Horvath, Steven and Tsao, Philip S and Absher, Devin M and Vokonas, Pantel and Hirschhorn, Joel and Fallin, M Daniele and Liu, Chunyu and Bandinelli, Stefania and Boerwinkle, Eric and Dehghan, Abbas and Schwartz, Joel D and Psaty, Bruce M and Feinberg, Andrew P and Hou, Lifang and Ferrucci, Luigi and Sotoodehnia, Nona and Matullo, Giuseppe and Peters, Annette and Fornage, Myriam and Assimes, Themistocles L and Whitsel, Eric A and Levy, Daniel and Baccarelli, Andrea A} } @article {8480, title = {Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs.}, journal = {Genome Med}, volume = {12}, year = {2020}, month = {2020 Sep 28}, pages = {84}, abstract = {

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 {\texttimes} 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 {\texttimes} 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 {\texttimes} 10), as well as the TFAM knockout methylation (P =~4.41 {\texttimes} 10) and expression (P =~4.30 {\texttimes} 10) studies.

CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

}, issn = {1756-994X}, doi = {10.1186/s13073-020-00778-7}, author = {Castellani, Christina A and Longchamps, Ryan J and Sumpter, Jason A and Newcomb, Charles E and Lane, John A and Grove, Megan L and Bressler, Jan and Brody, Jennifer A and Floyd, James S and Bartz, Traci M and Taylor, Kent D and Wang, Penglong and Tin, Adrienne and Coresh, Josef and Pankow, James S and Fornage, Myriam and Guallar, Eliseo and O{\textquoteright}Rourke, Brian and Pankratz, Nathan and Liu, Chunyu and Levy, Daniel and Sotoodehnia, Nona and Boerwinkle, Eric and Arking, Dan E} } @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 {9006, title = {Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 12 09}, pages = {7173}, abstract = {

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are~correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6\% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

}, keywords = {Amino Acid Transport System y+, Cohort Studies, CpG Islands, DNA Methylation, Epigenome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Transport Proteins, Facilitative, Gout, Humans, Male, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-021-27198-4}, author = {Tin, Adrienne and Schlosser, Pascal and Matias-Garcia, Pamela R and Thio, Chris H L and Joehanes, Roby and Liu, Hongbo and Yu, Zhi and Weihs, Antoine and Hoppmann, Anselm and Grundner-Culemann, Franziska and Min, Josine L and Kuhns, Victoria L Halperin and Adeyemo, Adebowale A and Agyemang, Charles and Arnl{\"o}v, Johan and Aziz, Nasir A and Baccarelli, Andrea and Bochud, Murielle and Brenner, Hermann and Bressler, Jan and Breteler, Monique M B and Carmeli, Cristian and Chaker, Layal and Coresh, Josef and Corre, Tanguy and Correa, Adolfo and Cox, Simon R and Delgado, Graciela E and Eckardt, Kai-Uwe and Ekici, Arif B and Endlich, Karlhans and Floyd, James S and Fraszczyk, Eliza and Gao, Xu and G{\`a}o, Xin and Gelber, Allan C and Ghanbari, Mohsen and Ghasemi, Sahar and Gieger, Christian and Greenland, Philip and Grove, Megan L and Harris, Sarah E and Hemani, Gibran and Henneman, Peter and Herder, Christian and Horvath, Steve and Hou, Lifang and Hurme, Mikko A and Hwang, Shih-Jen and Kardia, Sharon L R and Kasela, Silva and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and Kronenberg, Florian and Kuhnel, Brigitte and Ladd-Acosta, Christine and Lehtim{\"a}ki, Terho and Lind, Lars and Liu, Dan and Lloyd-Jones, Donald M and Lorkowski, Stefan and Lu, Ake T and Marioni, Riccardo E and M{\"a}rz, Winfried and McCartney, Daniel L and Meeks, Karlijn A C and Milani, Lili and Mishra, Pashupati P and Nauck, Matthias and Nowak, Christoph and Peters, Annette and Prokisch, Holger and Psaty, Bruce M and Raitakari, Olli T and Ratliff, Scott M and Reiner, Alex P and Sch{\"o}ttker, Ben and Schwartz, Joel and Sedaghat, Sanaz and Smith, Jennifer A and Sotoodehnia, Nona and Stocker, Hannah R and Stringhini, Silvia and Sundstr{\"o}m, Johan and Swenson, Brenton R and van Meurs, Joyce B J and van Vliet-Ostaptchouk, Jana V and Venema, Andrea and V{\"o}lker, Uwe and Winkelmann, Juliane and Wolffenbuttel, Bruce H R and Zhao, Wei and Zheng, Yinan and Loh, Marie and Snieder, Harold and Waldenberger, Melanie and Levy, Daniel and Akilesh, Shreeram and Woodward, Owen M and Susztak, Katalin and Teumer, Alexander and K{\"o}ttgen, Anna} } @article {8836, title = {Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.}, journal = {PLoS One}, volume = {16}, year = {2021}, month = {2021}, pages = {e0253611}, abstract = {

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12\%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0253611}, author = {Sarnowski, Chloe and Chen, Han and Biggs, Mary L and Wassertheil-Smoller, Sylvia and Bressler, Jan and Irvin, Marguerite R and Ryan, Kathleen A and Karasik, David and Arnett, Donna K and Cupples, L Adrienne and Fardo, David W and Gogarten, Stephanie M and Heavner, Benjamin D and Jain, Deepti and Kang, Hyun Min and Kooperberg, Charles and Mainous, Arch G and Mitchell, Braxton D and Morrison, Alanna C and O{\textquoteright}Connell, Jeffrey R and Psaty, Bruce M and Rice, Kenneth and Smith, Albert V and Vasan, Ramachandran S and Windham, B Gwen and Kiel, Douglas P and Murabito, Joanne M and Lunetta, Kathryn L} } @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 {9094, title = {Integrative analysis of clinical and epigenetic biomarkers of mortality.}, journal = {Aging Cell}, volume = {21}, year = {2022}, month = {2022 Jun}, pages = {e13608}, abstract = {

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n~=~15,013). During a mean follow-up of 10~years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p~<~1~{\texttimes}~10 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5\% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta~=~1.2, P ~=~4.1~{\texttimes}~10 ) and negatively associated with longevity (Beta~=~-1.9, P ~=~0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

}, keywords = {Biomarkers, Cardiovascular Diseases, DNA Methylation, Epigenesis, Genetic, Epigenomics, Humans, Male, Neoplasms}, issn = {1474-9726}, doi = {10.1111/acel.13608}, author = {Huan, Tianxiao and Nguyen, Steve and Colicino, Elena and Ochoa-Rosales, Carolina and Hill, W David and Brody, Jennifer A and Soerensen, Mette and Zhang, Yan and Baldassari, Antoine and Elhadad, Mohamed Ahmed and Toshiko, Tanaka and Zheng, Yinan and Domingo-Relloso, Arce and Lee, Dong Heon and Ma, Jiantao and Yao, Chen and Liu, Chunyu and Hwang, Shih-Jen and Joehanes, Roby and Fornage, Myriam and Bressler, Jan and van Meurs, Joyce B J and Debrabant, Birgit and Mengel-From, Jonas and Hjelmborg, Jacob and Christensen, Kaare and Vokonas, Pantel and Schwartz, Joel and Gahrib, Sina A and Sotoodehnia, Nona and Sitlani, Colleen M and Kunze, Sonja and Gieger, Christian and Peters, Annette and Waldenberger, Melanie and Deary, Ian J and Ferrucci, Luigi and Qu, Yishu and Greenland, Philip and Lloyd-Jones, Donald M and Hou, Lifang and Bandinelli, Stefania and Voortman, Trudy and Hermann, Brenner and Baccarelli, Andrea and Whitsel, Eric and Pankow, James S and Levy, Daniel} } @article {9035, title = {New insights into the genetic etiology of Alzheimer{\textquoteright}s disease and related dementias.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 Apr}, pages = {412-436}, abstract = {

Characterization of the genetic landscape of Alzheimer{\textquoteright}s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/{\textquoteright}proxy{\textquoteright} AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

}, keywords = {Alzheimer Disease, Cognitive Dysfunction, Genome-Wide Association Study, Humans, tau Proteins}, issn = {1546-1718}, doi = {10.1038/s41588-022-01024-z}, author = {Bellenguez, C{\'e}line and K{\"u}{\c c}{\"u}kali, Fahri and Jansen, Iris E and Kleineidam, Luca and Moreno-Grau, Sonia and Amin, Najaf and Naj, Adam C and Campos-Martin, Rafael and Grenier-Boley, Benjamin and Andrade, Victor and Holmans, Peter A and Boland, Anne and Damotte, Vincent and van der Lee, Sven J and Costa, Marcos R and Kuulasmaa, Teemu and Yang, Qiong and de Rojas, Itziar and Bis, Joshua C and Yaqub, Amber and Prokic, Ivana and Chapuis, Julien and Ahmad, Shahzad and Giedraitis, Vilmantas and Aarsland, Dag and Garcia-Gonzalez, Pablo and Abdelnour, Carla and Alarc{\'o}n-Mart{\'\i}n, Emilio and Alcolea, Daniel and Alegret, Montserrat and Alvarez, Ignacio and Alvarez, Victoria and Armstrong, Nicola J and Tsolaki, Anthoula and Antunez, Carmen and Appollonio, Ildebrando and Arcaro, Marina and Archetti, Silvana and Pastor, Alfonso Arias and Arosio, Beatrice and Athanasiu, Lavinia and Bailly, Henri and Banaj, Nerisa and Baquero, Miquel and Barral, Sandra and Beiser, Alexa and Pastor, Ana Bel{\'e}n and Below, Jennifer E and Benchek, Penelope and Benussi, Luisa and Berr, Claudine and Besse, C{\'e}line and Bessi, Valentina and Binetti, Giuliano and Bizarro, Alessandra and Blesa, Rafael and Boada, Merce and Boerwinkle, Eric and Borroni, Barbara and Boschi, Silvia and Boss{\`u}, Paola and Br{\r a}then, Geir and Bressler, Jan and Bresner, Catherine and Brodaty, Henry and Brookes, Keeley J and Brusco, Luis Ignacio and Buiza-Rueda, Dolores and B{\^u}rger, Katharina and Burholt, Vanessa and Bush, William S and Calero, Miguel and Cantwell, Laura B and Chene, Genevi{\`e}ve and Chung, Jaeyoon and Cuccaro, Michael L and Carracedo, Angel and Cecchetti, Roberta and Cervera-Carles, Laura and Charbonnier, Camille and Chen, Hung-Hsin and Chillotti, Caterina and Ciccone, Simona and Claassen, Jurgen A H R and Clark, Christopher and Conti, Elisa and Corma-G{\'o}mez, Ana{\"\i}s and Costantini, Emanuele and Custodero, Carlo and Daian, Delphine and Dalmasso, Maria Carolina and Daniele, Antonio and Dardiotis, Efthimios and Dartigues, Jean-Fran{\c c}ois and de Deyn, Peter Paul and de Paiva Lopes, Katia and de Witte, Lot D and Debette, Stephanie and Deckert, J{\"u}rgen and Del Ser, Teodoro and Denning, Nicola and DeStefano, Anita and Dichgans, Martin and Diehl-Schmid, Janine and Diez-Fairen, Monica and Rossi, Paolo Dionigi and Djurovic, Srdjan and Duron, Emmanuelle and D{\"u}zel, Emrah and Dufouil, Carole and Eiriksdottir, Gudny and Engelborghs, Sebastiaan and Escott-Price, Valentina and Espinosa, Ana and Ewers, Michael and Faber, Kelley M and Fabrizio, Tagliavini and Nielsen, Sune Fallgaard and Fardo, David W and Farotti, Lucia and Fenoglio, Chiara and Fern{\'a}ndez-Fuertes, Marta and Ferrari, Raffaele and Ferreira, Catarina B and Ferri, Evelyn and Fin, Bertrand and Fischer, Peter and Fladby, Tormod and Flie{\ss}bach, Klaus and Fongang, Bernard and Fornage, Myriam and Fortea, Juan and Foroud, Tatiana M and Fostinelli, Silvia and Fox, Nick C and Franco-Mac{\'\i}as, Emlio and Bullido, Mar{\'\i}a J and Frank-Garc{\'\i}a, Ana and Froelich, Lutz and Fulton-Howard, Brian and Galimberti, Daniela and Garc{\'\i}a-Alberca, Jose Maria and Garcia-Gonzalez, Pablo and Garcia-Madrona, Sebastian and Garcia-Ribas, Guillermo and Ghidoni, Roberta and Giegling, Ina and Giorgio, Giaccone and Goate, Alison M and Goldhardt, Oliver and Gomez-Fonseca, Duber and Gonz{\'a}lez-Perez, Antonio and Graff, Caroline and Grande, Giulia and Green, Emma and Grimmer, Timo and Gr{\"u}nblatt, Edna and Grunin, Michelle and Gudnason, Vilmundur and Guetta-Baranes, Tamar and Haapasalo, Annakaisa and Hadjigeorgiou, Georgios and Haines, Jonathan L and Hamilton-Nelson, Kara L and Hampel, Harald and Hanon, Olivier and Hardy, John and Hartmann, Annette M and Hausner, Lucrezia and Harwood, Janet and Heilmann-Heimbach, Stefanie and Helisalmi, Seppo and Heneka, Michael T and Hernandez, Isabel and Herrmann, Martin J and Hoffmann, Per and Holmes, Clive and Holstege, Henne and Vilas, Raquel Huerto and Hulsman, Marc and Humphrey, Jack and Biessels, Geert Jan and Jian, Xueqiu and Johansson, Charlotte and Jun, Gyungah R and Kastumata, Yuriko and Kauwe, John and Kehoe, Patrick G and Kilander, Lena and St{\r a}hlbom, Anne Kinhult and Kivipelto, Miia and Koivisto, Anne and Kornhuber, Johannes and Kosmidis, Mary H and Kukull, Walter A and Kuksa, Pavel P and Kunkle, Brian W and Kuzma, Amanda B and Lage, Carmen and Laukka, Erika J and Launer, Lenore and Lauria, Alessandra and Lee, Chien-Yueh and Lehtisalo, Jenni and Lerch, Ondrej and Lleo, Alberto and Longstreth, William and Lopez, Oscar and de Munain, Adolfo Lopez and Love, Seth and L{\"o}wemark, Malin and Luckcuck, Lauren and Lunetta, Kathryn L and Ma, Yiyi and Mac{\'\i}as, Juan and MacLeod, Catherine A and Maier, Wolfgang and Mangialasche, Francesca and Spallazzi, Marco and Marqui{\'e}, Marta and Marshall, Rachel and Martin, Eden R and Montes, Angel Mart{\'\i}n and Rodr{\'\i}guez, Carmen Mart{\'\i}nez and Masullo, Carlo and Mayeux, Richard and Mead, Simon and Mecocci, Patrizia and Medina, Miguel and Meggy, Alun and Mehrabian, Shima and Mendoza, Silvia and Men{\'e}ndez-Gonz{\'a}lez, Manuel and Mir, Pablo and Moebus, Susanne and Mol, Merel and Molina-Porcel, Laura and Montrreal, Laura and Morelli, Laura and Moreno, Fermin and Morgan, Kevin and Mosley, Thomas and N{\"o}then, Markus M and Muchnik, Carolina and Mukherjee, Shubhabrata and Nacmias, Benedetta and Ngandu, Tiia and Nicolas, Ga{\"e}l and Nordestgaard, B{\o}rge G and Olaso, Robert and Orellana, Adelina and Orsini, Michela and Ortega, Gemma and Padovani, Alessandro and Paolo, Caffarra and Papenberg, Goran and Parnetti, Lucilla and Pasquier, Florence and Pastor, Pau and Peloso, Gina and P{\'e}rez-Cord{\'o}n, Alba and P{\'e}rez-Tur, Jordi and Pericard, Pierre and Peters, Oliver and Pijnenburg, Yolande A L and Pineda, Juan A and Pi{\~n}ol-Ripoll, Gerard and Pisanu, Claudia and Polak, Thomas and Popp, Julius and Posthuma, Danielle and Priller, Josef and Puerta, Raquel and Quenez, Olivier and Quintela, In{\'e}s and Thomassen, Jesper Qvist and R{\'a}bano, Alberto and Rainero, Innocenzo and Rajabli, Farid and Ramakers, Inez and Real, Luis M and Reinders, Marcel J T and Reitz, Christiane and Reyes-Dumeyer, Dolly and Ridge, Perry and Riedel-Heller, Steffi and Riederer, Peter and Roberto, Natalia and Rodriguez-Rodriguez, Eloy and Rongve, Arvid and Allende, Irene Rosas and Rosende-Roca, Mait{\'e}e and Royo, Jose Luis and Rubino, Elisa and Rujescu, Dan and S{\'a}ez, Mar{\'\i}a Eugenia and Sakka, Paraskevi and Saltvedt, Ingvild and Sanabria, {\'A}ngela and S{\'a}nchez-Arjona, Mar{\'\i}a Bernal and Sanchez-Garcia, Florentino and Juan, Pascual S{\'a}nchez and S{\'a}nchez-Valle, Raquel and Sando, Sigrid B and Sarnowski, Chloe and Satizabal, Claudia L and Scamosci, Michela and Scarmeas, Nikolaos and Scarpini, Elio and Scheltens, Philip and Scherbaum, Norbert and Scherer, Martin and Schmid, Matthias and Schneider, Anja and Schott, Jonathan M and Selb{\ae}k, Geir and Seripa, Davide and Serrano, Manuel and Sha, Jin and Shadrin, Alexey A and Skrobot, Olivia and Slifer, Susan and Snijders, Gijsje J L and Soininen, Hilkka and Solfrizzi, Vincenzo and Solomon, Alina and Song, Yeunjoo and Sorbi, Sandro and Sotolongo-Grau, Oscar and Spalletta, Gianfranco and Spottke, Annika and Squassina, Alessio and Stordal, Eystein and Tartan, Juan Pablo and Tarraga, Lluis and Tes{\'\i}, Niccolo and Thalamuthu, Anbupalam and Thomas, Tegos and Tosto, Giuseppe and Traykov, Latchezar and Tremolizzo, Lucio and Tybj{\ae}rg-Hansen, Anne and Uitterlinden, Andre and Ullgren, Abbe and Ulstein, Ingun and Valero, Sergi and Valladares, Otto and Broeckhoven, Christine Van and Vance, Jeffery and Vardarajan, Badri N and van der Lugt, Aad and Dongen, Jasper Van and van Rooij, Jeroen and van Swieten, John and Vandenberghe, Rik and Verhey, Frans and Vidal, Jean-S{\'e}bastien and Vogelgsang, Jonathan and Vyhnalek, Martin and Wagner, Michael and Wallon, David and Wang, Li-San and Wang, Ruiqi and Weinhold, Leonie and Wiltfang, Jens and Windle, Gill and Woods, Bob and Yannakoulia, Mary and Zare, Habil and Zhao, Yi and Zhang, Xiaoling and Zhu, Congcong and Zulaica, Miren and Farrer, Lindsay A and Psaty, Bruce M and Ghanbari, Mohsen and Raj, Towfique and Sachdev, Perminder and Mather, Karen and Jessen, Frank and Ikram, M Arfan and de Mendon{\c c}a, Alexandre and Hort, Jakub and Tsolaki, Magda and Pericak-Vance, Margaret A and Amouyel, Philippe and Williams, Julie and Frikke-Schmidt, Ruth and Clarimon, Jordi and Deleuze, Jean-Francois and Rossi, Giacomina and Seshadri, Sudha and Andreassen, Ole A and Ingelsson, Martin and Hiltunen, Mikko and Sleegers, Kristel and Schellenberg, Gerard D and van Duijn, Cornelia M and Sims, Rebecca and van der Flier, Wiesje M and Ruiz, Agustin and Ramirez, Alfredo and Lambert, Jean-Charles} } @article {9323, title = {Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.}, journal = {Neurology}, year = {2023}, month = {2023 Mar 16}, abstract = {

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer{\textquoteright}s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within {\textpm}5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. >=60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57\% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95\% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000207157}, author = {Zhang, Yuankai and Liu, Xue and Wiggins, Kerri L and Kurniansyah, Nuzulul and Guo, Xiuqing and Rodrigue, Amanda L and Zhao, Wei and Yanek, Lisa R and Ratliff, Scott M and Pitsillides, Achilleas and Aguirre Pati{\~n}o, Juan Sebastian and Sofer, Tamar and Arking, Dan E and Austin, Thomas R and Beiser, Alexa S and Blangero, John and Boerwinkle, Eric and Bressler, Jan and Curran, Joanne E and Hou, Lifang and Hughes, Timothy M and Kardia, Sharon L and Launer, Lenore and Levy, Daniel and Mosley, Tom H and Nasrallah, Ilya M and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Tarraf, Wassim and Gonz{\'a}lez, Kevin A and Ramachandran, Vasan and Yaffe, Kristine and Nyquist, Paul A and Psaty, Bruce M and DeCarli, Charles S and Smith, Jennifer A and Glahn, David C and Gonz{\'a}lez, Hector M and Bis, Joshua C and Fornage, Myriam and Heckbert, Susan R and Fitzpatrick, Annette L and Liu, Chunyu and Satizabal, Claudia L} } @article {9742, title = {Epigenome-wide DNA Methylation Association Study of CHIP Provides Insight into Perturbed Gene Regulation.}, journal = {Res Sq}, year = {2024}, month = {2024 Jul 16}, abstract = {

With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed "clonal hematopoiesis of indeterminate potential" (CHIP). How these mutations confer a proliferative advantage and result in increased risk for numerous age-related diseases remains poorly understood. We conducted a multiracial meta-analysis of epigenome-wide association studies (EWAS) of CHIP and its subtypes in four cohorts (N=8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. The EWAS findings were functionally validated using human hematopoietic stem cell (HSC) models of CHIP. A total of 9615 CpGs were associated with any CHIP, 5990 with DNMT3A CHIP, 5633 with TET2 CHIP, and 6078 with ASXL1 CHIP (P <1{\texttimes}10). CpGs associated with CHIP subtypes overlapped moderately, and the genome-wide DNA methylation directions of effect were opposite for TET2 and DNMT3A CHIP, consistent with their opposing effects on global DNA methylation. There was high directional concordance between the CpGs shared from the meta-EWAS and human edited CHIP HSCs. Expression quantitative trait methylation analysis further identified transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses revealed 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value <0.05). Taken together, our study sheds light on the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes. The novel genes and pathways linked to the epigenetic features of CHIP may serve as therapeutic targets for preventing or treating CHIP-mediated diseases.

}, issn = {2693-5015}, doi = {10.21203/rs.3.rs-4656898/v1}, author = {Levy, Daniel and Kirmani, Sara and Huan, Tianxiao and Van Amburg, Joseph and Joehanes, Roby and Uddin, Md Mesbah and Nguyen, Ngoc Quynh and Yu, Bing and Brody, Jennifer and Fornage, Myriam and Bressler, Jan and Sotoodehnia, Nona and Ong, David and Puddu, Fabio and Floyd, James and Ballantyne, Christie and Psaty, Bruce and Raffield, Laura and Natarajan, Pradeep and Conneely, Karen and Carson, April and Lange, Leslie and Ferrier, Kendra and Heard-Costa, Nancy and Murabito, Joanne and Bick, Alexander} } @article {9578, title = {Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.}, journal = {Alzheimers Res Ther}, volume = {16}, year = {2024}, month = {2024 Jan 20}, pages = {14}, abstract = {

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

}, keywords = {Aged, Cognition, Genome-Wide Association Study, Humans, Memory, MicroRNAs, Multiomics, Polymorphism, Single Nucleotide}, issn = {1758-9193}, doi = {10.1186/s13195-023-01376-6}, author = {Mei, Hao and Simino, Jeannette and Li, Lianna and Jiang, Fan and Bis, Joshua C and Davies, Gail and Hill, W David and Xia, Charley and Gudnason, Vilmundur and Yang, Qiong and Lahti, Jari and Smith, Jennifer A and Kirin, Mirna and De Jager, Philip and Armstrong, Nicola J and Ghanbari, Mohsen and Kolcic, Ivana and Moran, Christopher and Teumer, Alexander and Sargurupremraj, Murali and Mahmud, Shamsed and Fornage, Myriam and Zhao, Wei and Satizabal, Claudia L and Polasek, Ozren and R{\"a}ikk{\"o}nen, Katri and Liewald, David C and Homuth, Georg and Callisaya, Michele and Mather, Karen A and Windham, B Gwen and Zemunik, Tatijana and Palotie, Aarno and Pattie, Alison and van der Auwera, Sandra and Thalamuthu, Anbupalam and Knopman, David S and Rudan, Igor and Starr, John M and Wittfeld, Katharina and Kochan, Nicole A and Griswold, Michael E and Vitart, Veronique and Brodaty, Henry and Gottesman, Rebecca and Cox, Simon R and Psaty, Bruce M and Boerwinkle, Eric and Chasman, Daniel I and Grodstein, Francine and Sachdev, Perminder S and Srikanth, Velandai and Hayward, Caroline and Wilson, James F and Eriksson, Johan G and Kardia, Sharon L R and Grabe, Hans J and Bennett, David A and Ikram, M Arfan and Deary, Ian J and van Duijn, Cornelia M and Launer, Lenore and Fitzpatrick, Annette L and Seshadri, Sudha and Bressler, Jan and Debette, Stephanie and Mosley, Thomas H} } @article {9940, title = {Selected social and lifestyle correlates of brain health markers: the Cross-Cohort Collaboration Consortium.}, journal = {Alzheimers Dement}, volume = {21}, year = {2025}, month = {2025 Apr}, pages = {e70148}, abstract = {

INTRODUCTION: To investigate the associations of education level, marital status, and physical activity with dementia risk and brain MRI markers.

METHODS: Data from six community-based samples from the Cross-Cohort Collaboration Consortium were analyzed. Self-reported education level, marital status, and physical activity at age 60 to 75 years were harmonized. Subsamples of participants with brain MRI markers at time of exposure were selected. Associations with dementia risk and cross-sectional MRI markers were meta-analyzed.

RESULTS: Higher education level was associated with lower dementia risk (hazard ratio [HR]~=~0.65, 95\% confidence interval [CI]~=~0.59; 0.72~vs low level) but not significantly with brain MRI markers. Compared with being unmarried, being married was only associated with higher total brain and hippocampal volumes. Being physically active was associated with lower dementia risk (HR~=~0.73, 95\% CI~=~0.52; 1.04), as well as larger total brain volume and smaller white matter hyperintensity volume.

DISCUSSION: This study provides further evidence regarding the contribution of education level and physical activity to dementia resilience.

HIGHLIGHTS: Education level, marital status, and physical activity are thought to contribute to resilience against ADRD. We used random-effects meta-analysis to summarize results from six community-based samples from the CCC. In this cross-cohort meta-analysis, higher education level and being physically active were associated with lower risk of dementia. In cross-sectional analyses, being married was associated with larger TBV and HV, while being physically active was associated with larger TBV and lower WMHV.

}, keywords = {Aged, Brain, Cohort Studies, Cross-Sectional Studies, Dementia, Educational Status, Exercise, Female, Humans, Life Style, Magnetic Resonance Imaging, Male, Marital Status, Middle Aged, Risk Factors}, issn = {1552-5279}, doi = {10.1002/alz.70148}, author = {Grasset, Leslie and Bis, Joshua C and Frenzel, Stefan and Kojis, Daniel and Simino, Jeannette and Yaqub, Amber and Beiser, Alexa and Berr, Claudine and Bressler, Jan and B{\"u}low, Robin and DeCarli, Charles S and Fohner, Alison E and Harrington, Laura B and Helmer, Catherine and Ikram, M Arfan and Lemaitre, Rozenn N and Lopez, Oscar L and Longstreth, W T and Neitzel, Julia and Odden, Michelle C and Palta, Priya and Schmidt, Carsten O and Talluri, Rajesh and Vernooij, Meike W and V{\"o}lzke, Henry and Voortman, Trudy and Whalen, Quest and Wittfeld, Katharina and Grabe, Hans J and Mosley, Thomas H and Psaty, Bruce M and Wolters, Frank J and Seshadri, Sudha and Dufouil, Carole} }