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Your search keyword '"DeStefano, Anita L."' showing total 15 results
Start Over Author "DeStefano, Anita L." Topic dementia
15 results on '"DeStefano, Anita L."'

1. Exploiting family history in aggregation unit-based genetic association tests.

Author

Wang Y, Chen H, Peloso GM, DeStefano AL, and Dupuis J

Subjects
Humans, Genetic Testing, Medical History Taking, Case-Control Studies, Risk Factors, Hypertension, Dementia
Abstract

The development of sequencing technology calls for new powerful methods to detect disease associations and lower the cost of sequencing studies. Family history (FH) contains information on disease status of relatives, adding valuable information about the probands' health problems and risk of diseases. Incorporating data from FH is a cost-effective way to improve statistical evidence in genetic studies, and moreover, overcomes limitations in study designs with insufficient cases or missing genotype information for association analysis. We proposed family history aggregation unit-based test (FHAT) and optimal FHAT (FHAT-O) to exploit available FH for rare variant association analysis. Moreover, we extended liability threshold model of case-control status and FH (LT-FH) method in aggregated unit-based methods and compared that with FHAT and FHAT-O. The computational efficiency and flexibility of the FHAT and FHAT-O were demonstrated through both simulations and applications. We showed that FHAT, FHAT-O, and LT-FH methods offer reasonable control of the type I error unless case/control ratio is unbalanced, in which case they result in smaller inflation than that observed with conventional methods excluding FH. We also demonstrated that FHAT and FHAT-O are more powerful than LT-FH and conventional methods in many scenarios. By applying FHAT and FHAT-O to the analysis of all cause dementia and hypertension using the exome sequencing data from the UK Biobank, we showed that our methods can improve significance for known regions. Furthermore, we replicated the previous associations in all cause dementia and hypertension and detected novel regions through the exome-wide analysis., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Published
2022
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2. Cardiovascular health, genetic risk, and risk of dementia in the Framingham Heart Study.

Author

Peloso GM, Beiser AS, Satizabal CL, Xanthakis V, Vasan RS, Pase MP, Destefano AL, and Seshadri S

Subjects
Aged, Cardiovascular Diseases epidemiology, Comorbidity, Female, Humans, Incidence, Longitudinal Studies, Male, Middle Aged, Risk Factors, Cardiovascular Diseases complications, Dementia epidemiology, Dementia etiology, Genetic Predisposition to Disease
Abstract

Objective: To determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia., Methods: We categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic risk through a genetic risk score (GRS) of common genetic variants and the APOE ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education., Results: We observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval [CI] of hazard ratio [HR] 1.23-5.29; p = 0.012) compared with having a low GRS (<20th percentile); carrying at least 1 APOE ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an APOE ε4 allele (95% CI of HR 1.49-3.53; p = 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20-1.01; p = 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS ( p = 0.99) or APOE ε4 ( p = 0.16)., Conclusions: We observed that both genetic risk and CVH contribute additively to dementia risk., (© 2020 American Academy of Neurology.)

Published
2020
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3. Serum brain-derived neurotrophic factor and the risk for dementia: the Framingham Heart Study.

Author

Weinstein G, Beiser AS, Choi SH, Preis SR, Chen TC, Vorgas D, Au R, Pikula A, Wolf PA, DeStefano AL, Vasan RS, and Seshadri S

Subjects
Aged, Aged, 80 and over, Alzheimer Disease genetics, Brain-Derived Neurotrophic Factor genetics, Dementia genetics, Female, Genotype, Humans, Incidence, Male, Polymorphism, Single Nucleotide genetics, Proportional Hazards Models, Prospective Studies, Risk, Sensitivity and Specificity, Alzheimer Disease blood, Alzheimer Disease prevention & control, Brain-Derived Neurotrophic Factor blood, Dementia blood, Dementia prevention & control
Abstract

Importance: In animal studies, brain-derived neurotrophic factor (BDNF) has been shown to impact neuronal survival and function and improve synaptic plasticity and long-term memory. Circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia. Some prior studies showed lower circulating BDNF in persons with Alzheimer disease (AD) compared with control participants; however, it remains uncertain whether reduced levels precede dementia onset., Objective: To examine whether higher serum BDNF levels in cognitively healthy adults protect against the future risk for dementia and AD and to identify potential modifiers of this association., Design, Setting, and Participants: Framingham Study original and offspring participants were followed up from 1992 and 1998, respectively, for up to 10 years. We used Cox models to relate BDNF levels to the risk for dementia and AD and adjusted for potential confounders. We also ran sensitivity analyses stratified by sex, age, and education, as well as related BDNF genetic variants to AD risk. This community-based, prospective cohort study involved 2131 dementia-free participants aged 60 years and older (mean [SD] age, 72 [7] years; 56% women)., Main Outcomes and Measures: Ten-year incidence of dementia and AD., Results: During follow-up, 140 participants developed dementia, 117 of whom had AD. Controlling for age and sex, each standard-deviation increment in BDNF was associated with a 33% lower risk for dementia and AD (P = .006 and P = .01, respectively) and these associations persisted after additional adjustments. Compared with the bottom quintile, BDNF levels in the top quintile were associated with less than half the risk for dementia and AD (hazard ratio, 0.49; 95% CI, 0.28-0.85; P = .01; and hazard ratio, 0.46; 95% CI, 0.24-0.86; P = .02, respectively). These associations were apparent only among women, persons aged 80 years and older, and those with college degrees (hazard ratios for AD: 0.65, [95% CI, 0.50-0.85], P = .001; 0.63 [95% CI, 0.47-0.85], P = .002; and 0.27 [95% CI, 0.11-0.65], P = .003, respectively). Brain-derived neurotrophic factor genetic variants were not associated with AD risk., Conclusions and Relevance: Higher serum BDNF levels may protect against future occurrence of dementia and AD. Our findings suggest a role for BDNF in the biology and possibly in the prevention of dementia and AD, especially in select subgroups of women and older and more highly educated persons.

Published
2014
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4. Common variants at 12q14 and 12q24 are associated with hippocampal volume.

Author

Bis JC, DeCarli C, Smith AV, van der Lijn F, Crivello F, Fornage M, Debette S, Shulman JM, Schmidt H, Srikanth V, Schuur M, Yu L, Choi SH, Sigurdsson S, Verhaaren BF, DeStefano AL, Lambert JC, Jack CR Jr, Struchalin M, Stankovich J, Ibrahim-Verbaas CA, Fleischman D, Zijdenbos A, den Heijer T, Mazoyer B, Coker LH, Enzinger C, Danoy P, Amin N, Arfanakis K, van Buchem MA, de Bruijn RF, Beiser A, Dufouil C, Huang J, Cavalieri M, Thomson R, Niessen WJ, Chibnik LB, Gislason GK, Hofman A, Pikula A, Amouyel P, Freeman KB, Phan TG, Oostra BA, Stein JL, Medland SE, Vasquez AA, Hibar DP, Wright MJ, Franke B, Martin NG, Thompson PM, Nalls MA, Uitterlinden AG, Au R, Elbaz A, Beare RJ, van Swieten JC, Lopez OL, Harris TB, Chouraki V, Breteler MM, De Jager PL, Becker JT, Vernooij MW, Knopman D, Fazekas F, Wolf PA, van der Lugt A, Gudnason V, Longstreth WT Jr, Brown MA, Bennett DA, van Duijn CM, Mosley TH, Schmidt R, Tzourio C, Launer LJ, Ikram MA, and Seshadri S

Subjects
Alzheimer Disease genetics, Genetic Loci, Genetic Markers, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Chromosomes, Human, Pair 12 genetics, Cognition Disorders genetics, Dementia genetics, Hippocampus physiopathology, Polymorphism, Single Nucleotide genetics
Abstract

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Published
2012
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5. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen GJ, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W, Berr, Claudine, Bis, Joshua C, Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A, Fernández, Maria Victoria, Fox, Nick C, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L, Holmes, Clive, Ikram, M Arfan, Ikram, M Kamran, Jansen, Iris E, Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W, Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel MAM, Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O, Morgan, Kevin, Myers, Richard M, Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A, Raybould, Rachel, Redon, Richard, Reinders, Marcel JT, Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D, Scheltens, Philip, Schott, Jonathan M, Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo’, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J, Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C, Greicius, Michael D, Yokoyama, Jennifer S, Cruchaga, Carlos, Hardy, John, and Ramirez, Alfredo

Subjects
Biological Sciences, Genetics, Dementia, Alzheimer's Disease, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Aging, Clinical Research, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Adenosine Triphosphatases, Alzheimer Disease, ATP Binding Cassette Transporter 1, Genome-Wide Association Study, Risk Factors, Exosomes, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Published
2022

6. Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels

Author

Sarnowski, Chloé, Ghanbari, Mohsen, Bis, Joshua C, Logue, Mark, Fornage, Myriam, Mishra, Aniket, Ahmad, Shahzad, Beiser, Alexa S, Boerwinkle, Eric, Bouteloup, Vincent, Chouraki, Vincent, Cupples, L Adrienne, Damotte, Vincent, DeCarli, Charles S, DeStefano, Anita L, Djoussé, Luc, Fohner, Alison E, Franz, Carol E, Kautz, Tiffany F, Lambert, Jean-Charles, Lyons, Michael J, Mosley, Thomas H, Mukamal, Kenneth J, Pase, Matthew P, Portilla Fernandez, Eliana C, Rissman, Robert A, Satizabal, Claudia L, Vasan, Ramachandran S, Yaqub, Amber, Debette, Stephanie, Dufouil, Carole, Launer, Lenore J, Kremen, William S, Longstreth, William T, Ikram, M Arfan, and Seshadri, Sudha

Subjects
Biological Sciences, Genetics, Aging, Neurosciences, Neurodegenerative, Alzheimer's Disease, Dementia, Brain Disorders, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Black or African American, Alzheimer Disease, Exome, Genome-Wide Association Study, Humans, Tauopathies, Biological sciences, Biomedical and clinical sciences
Abstract

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P

Published
2022

7. Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging

Author

Jian, Xueqiu, Satizabal, Claudia L, Smith, Albert V, Wittfeld, Katharina, Bis, Joshua C, Smith, Jennifer A, Hsu, Fang-Chi, Nho, Kwangsik, Hofer, Edith, Hagenaars, Saskia P, Nyquist, Paul A, Mishra, Aniket, Adams, Hieab HH, Li, Shuo, Teumer, Alexander, Zhao, Wei, Freedman, Barry I, Saba, Yasaman, Yanek, Lisa R, Chauhan, Ganesh, van Buchem, Mark A, Cushman, Mary, Royle, Natalie A, Bryan, R Nick, Niessen, Wiro J, Windham, Beverly G, DeStefano, Anita L, Habes, Mohamad, Heckbert, Susan R, Palmer, Nicholette D, Lewis, Cora E, Eiriksdottir, Gudny, Maillard, Pauline, Mathias, Rasika A, Homuth, Georg, Valdés-Hernández, Maria del C, Divers, Jasmin, Beiser, Alexa S, Langner, Sönke, Rice, Kenneth M, Bastin, Mark E, Yang, Qiong, Maldjian, Joseph A, Starr, John M, Sidney, Stephen, Risacher, Shannon L, Uitterlinden, André G, Gudnason, Vilmundur G, Nauck, Matthias, Rotter, Jerome I, Schreiner, Pamela J, Boerwinkle, Eric, van Duijn, Cornelia M, Mazoyer, Bernard, von Sarnowski, Bettina, Gottesman, Rebecca F, Levy, Daniel, Sigurdsson, Sigurdur, Vernooij, Meike W, Turner, Stephen T, Schmidt, Reinhold, Wardlaw, Joanna M, Psaty, Bruce M, Mosley, Thomas H, DeCarli, Charles S, Saykin, Andrew J, Bowden, Donald W, Becker, Diane M, Deary, Ian J, Schmidt, Helena, Kardia, Sharon LR, Ikram, M Arfan, Debette, Stéphanie, Grabe, Hans J, Longstreth, WT, Seshadri, Sudha, Launer, Lenore J, and Fornage, Myriam

Subjects
Epidemiology, Health Sciences, Alzheimer's Disease Related Dementias (ADRD), Dementia, Human Genome, Cerebrovascular, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stroke, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Aging, Minority Health, Genetics, Neurosciences, Biotechnology, 2.1 Biological and endogenous factors, Neurological, Brain, Cohort Studies, Exome, Genetic Variation, Humans, Magnetic Resonance Imaging, Mitochondrial Proteins, White Matter, cerebral small vessel disease, exome, magnetic resonance imaging, meta-analysis, white matter, neuroCHARGE Working Group, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurology & Neurosurgery, Clinical sciences, Allied health and rehabilitation science
Abstract

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P

Published
2018

8. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease

Author

Jakobsdottir, Johanna, van der Lee, Sven J, Bis, Joshua C, Chouraki, Vincent, Li-Kroeger, David, Yamamoto, Shinya, Grove, Megan L, Naj, Adam, Vronskaya, Maria, Salazar, Jose L, DeStefano, Anita L, Brody, Jennifer A, Smith, Albert V, Amin, Najaf, Sims, Rebecca, Ibrahim-Verbaas, Carla A, Choi, Seung-Hoan, Satizabal, Claudia L, Lopez, Oscar L, Beiser, Alexa, Ikram, M Arfan, Garcia, Melissa E, Hayward, Caroline, Varga, Tibor V, Ripatti, Samuli, Franks, Paul W, Hallmans, Göran, Rolandsson, Olov, Jansson, Jan-Håkon, Porteous, David J, Salomaa, Veikko, Eiriksdottir, Gudny, Rice, Kenneth M, Bellen, Hugo J, Levy, Daniel, Uitterlinden, Andre G, Emilsson, Valur, Rotter, Jerome I, Aspelund, Thor, consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Consortium, Alzheimer’s Disease Genetic, consortium, Genetic and Environmental Risk in Alzheimer’s Disease, O’Donnell, Christopher J, Fitzpatrick, Annette L, Launer, Lenore J, Hofman, Albert, Wang, Li-San, Williams, Julie, Schellenberg, Gerard D, Boerwinkle, Eric, Psaty, Bruce M, Seshadri, Sudha, Shulman, Joshua M, Gudnason, Vilmundur, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Aging, Acquired Cognitive Impairment, Human Genome, Neurosciences, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Dementia, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Neurological, Age of Onset, Aged, Alleles, Alzheimer Disease, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Drosophila Proteins, Drosophila melanogaster, Exome, Female, Genome-Wide Association Study, Genomics, Humans, Iceland, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mutation, Phenotype, Receptors, Notch, Tropomyosin, White People, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium, Developmental Biology
Abstract

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus

Published
2016

9. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Author

Desikan, Rahul S, Schork, Andrew J, Wang, Yunpeng, Thompson, Wesley K, Dehghan, Abbas, Ridker, Paul M, Chasman, Daniel I, McEvoy, Linda K, Holland, Dominic, Chen, Chi-Hua, Karow, David S, Brewer, James B, Hess, Christopher P, Williams, Julie, Sims, Rebecca, O'Donovan, Michael C, Choi, Seung Hoan, Bis, Joshua C, Ikram, M Arfan, Gudnason, Vilmundur, DeStefano, Anita L, van der Lee, Sven J, Psaty, Bruce M, van Duijn, Cornelia M, Launer, Lenore, Seshadri, Sudha, Pericak-Vance, Margaret A, Mayeux, Richard, Haines, Jonathan L, Farrer, Lindsay A, Hardy, John, Ulstein, Ingun Dina, Aarsland, Dag, Fladby, Tormod, White, Linda R, Sando, Sigrid B, Rongve, Arvid, Witoelar, Aree, Djurovic, Srdjan, Hyman, Bradley T, Snaedal, Jon, Steinberg, Stacy, Stefansson, Hreinn, Stefansson, Kari, Schellenberg, Gerard D, Andreassen, Ole A, and Dale, Anders M

Subjects
Epidemiology, Health Sciences, Genetics, Prevention, Brain Disorders, Alzheimer's Disease, Neurodegenerative, Acquired Cognitive Impairment, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Cardiovascular, Neurosciences, Dementia, 2.1 Biological and endogenous factors, Aetiology, Aged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Brain, C-Reactive Protein, Dyslipidemias, Female, Genome-Wide Association Study, Humans, Inflammation, Lipids, Male, Multifactorial Inheritance, Peroxisomal Bifunctional Enzyme, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sulfotransferases, inflammation, lipids, Inflammation working group, IGAP and DemGene Investigators, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences, Sports science and exercise
Abstract

BackgroundEpidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis.Methods and resultsUsing summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold

Published
2015

10. Bone mineral density and the risk of incident dementia: A meta‐analysis.

Author

Lary, Christine W., Ghatan, Samuel, Gerety, Meghan, Hinton, Alexandra, Nagarajan, Archana, Rosen, Clifford, Ross, Ryan D., Bennett, David A., DeStefano, Anita L., Ikram, Mohammad A., Rivadeneira, Fernando, Kiel, Douglas P., Seshadri, Sudha, and Beiser, Alexa

Subjects
DEMENTIA risk factors, ALZHEIMER'S disease risk factors, META-analysis, PHOTON absorptiometry, CONFIDENCE intervals, OSTEOPOROSIS, RESEARCH funding, BONE density, FEMUR, DISEASE complications
Abstract

Background: It is not known whether bone mineral density (BMD) measured at baseline or as the rate of decline prior to baseline (prior bone loss) is a stronger predictor of incident dementia or Alzheimer's disease (AD). Methods: We performed a meta‐analysis of three longitudinal studies, the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Rush Memory and Aging Project (MAP), modeling the time to diagnosis of dementia as a function of BMD measures accounting for covariates. We included individuals with one or two BMD assessments, aged ≥60 years, and free of dementia at baseline with follow‐up available. BMD was measured at the hip femoral neck using dual‐energy X‐ray absorptiometry (DXA), or at the heel calcaneus using quantitative ultrasound to calculate estimated BMD (eBMD). BMD at study baseline ("baseline BMD") and annualized percentage change in BMD prior to baseline ("prior bone loss") were included as continuous measures. The primary outcome was incident dementia diagnosis within 10 years of baseline, and incident AD was a secondary outcome. Baseline covariates included age, sex, body mass index, ApoE4 genotype, and education. Results: The combined sample size across all three studies was 4431 with 606 incident dementia diagnoses, 498 of which were AD. A meta‐analysis of baseline BMD across three studies showed higher BMD to have a significant protective association with incident dementia with a hazard ratio of 0.47 (95% CI: 0.23–0.96; p = 0.038) per increase in g/cm2, or 0.91 (95% CI: 0.84–0.995) per standard deviation increase. We observed a significant association between prior bone loss and incident dementia with a hazard ratio of 1.30 (95% CI: 1.12–1.51; p < 0.001) per percent increase in prior bone loss only in the FHS cohort. Conclusions: Baseline BMD but not prior bone loss was associated with incident dementia in a meta‐analysis across three studies. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Author

Peloso, Gina M, van der Lee, Sven J, International Genomics of Alzheimer's Project (IGAP), Destefano, Anita L, Seshardi, Sudha, and Apollo - University of Cambridge Repository

Subjects
Aging, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, Instrumental variables, Single nucleotide polymorphisms, Neurodegenerative, Atherosclerosis, Alzheimer's Disease, Cholesteryl ester transfer protein, Brain Disorders, Neurological, Acquired Cognitive Impairment, International Genomics of Alzheimer's Project, Genetics, 2.1 Biological and endogenous factors, Dementia, lipids (amino acids, peptides, and proteins), HDL-C, Aetiology
Abstract

IntroductionThere is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.MethodsTen single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.ResultsBased on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P>.7).DiscussionOur study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.

Published
2018

12. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Author

Escott-Price, Valentina, Bellenguez, Céline, DeStefano, Anita L, Galimberti, Daniela, Scarpini, Elio, Bonuccelli, Ubaldo, Mancuso, Michelangelo, Siciliano, Gabriele, Moebus, Susanne, Mecocci, Patrizia, Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald, Lambert, Jean-Charles, Pilotto, Alberto, Frank-García, Ana, Panza, Francesco, Solfrizzi, Vincenzo, Caffarra, Paolo, Nacmias, Benedetta, Perry, William, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Ibrahim-Verbaas, Carla A, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton-Nelson, Kara L, Naj, Adam C, Gu, Wei, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Sims, Rebecca, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, de Bruijn, Renee F A G, Passmore, Peter, Jun, Gyungah, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Bis, Joshua C, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Beecham, Gary W, Dartigues, Jean-François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Psaty, Bruce M, Haines, Jonathan L, Lathrop, Mark, Pericak-Vance, Margaret A, Grenier-Boley, Benjamin, Launer, Lenore J, Van Broeckhoven, Christine, Farrer, Lindsay A, van Duijn, Cornelia M, Ramirez, Alfredo, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Study, Cardiovascular Health, Russo, Giancarlo, Olson, Jean, Kronmal, Richard, Arnold, Alice M, Robbins, John, Carlson, Michelle, Burke, Gregory, Kuller, Lewis H, Tracy, Russell, Gottdiener, John, Prineas, Ronald, Wang, Li-San, Thornton-Wells, Tricia A, Becker, James T, Enright, Paul, Klein, Ronald, O'Leary, Daniel H, Denning, Nicola, Smith, Albert V, Chouraki, Vincent, Thomas, Charlene, Ikram, M Arfan, Zelenika, Diana, Vardarajan, Badri N, Kamatani, Yoichiro, Lin, Chiao-Feng, Choi, Seung-Hoan, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L, Vronskaya, Maria, Consortium, United Kingdom Brain Expression, Johnson, Andrew D, Ruiz, Agustin, Bihoreau, Marie-Thérèse, Reitz, Christiane, Pasquier, Florence, Harold, Denise, Hollingworth, Paul, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Jones, Lesley, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Holmans, Peter, Hernández, Isabel, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiévet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M Ilyas, Gerrish, Amy, Keller, Lina, Barberger-Gateau, Pascale, McGuinness, Bernadette, Larson, Eric B, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Vedernikov, Alexey, Gallacher, John, George-Hyslop, Peter St, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Yu, Lei, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Richards, Alexander, Proitsi, Petra, Collinge, John, Sorbi, Sandro, Garcia, Florentino Sanchez, Fox, Nick C, Hardy, John, Naranjo, Maria Candida Deniz, Bosco, Paolo, Clarke, Robert, Brayne, Carol, Neurology, Radiology & Nuclear Medicine, Epidemiology, UAM. Departamento de Medicina, Universidad de Cantabria, and United Kingdom Brain Expression

Subjects
Genetics and Molecular Biology (all), Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Medicine (all), genotype, Medizin, lcsh:Medicine, genetics [Alzheimer Disease], Genome-wide association study, Genomics--Data processing, Disease, genetics [Carrier Proteins], Biochemistry, Alzheimer's disease, 0302 clinical medicine, genetics [Heat-Shock Proteins], genetics [Receptors, Antigen, B-Cell], Disease susceptibility--Genetic aspects, Receptors, Pathology, Medicine and Health Sciences, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, pathogenesis, Genomics, Single Nucleotide, Neurology, Antigen, Physical Sciences, protein degradation, Alzheimer disease, Engineering sciences. Technology, Statistics (Mathematics), Research Article, medicine.medical_specialty, Medicina, Geriatrik, Late onset, Biostatistics, Biology, Medical sciences, 03 medical and health sciences, Molecular genetics, Mental Health and Psychiatry, Genome-Wide Association Studies, medicine, chromosome 8, Dementia, ddc:610, Polymorphism, QH426, Genetic Association Studies, 030304 developmental biology, TP53INP1 protein, human, lcsh:R, Case-control study, B-Cell, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, R1, Human genetics, immune system, Geriatrics, FOS: Biological sciences, Alzheimer's disease--Genetic aspects, RC0321, lcsh:Q, Mathematics, 030217 neurology & neurosurgery
Abstract

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease, The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Génotypage,and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM «Cohortes et collections de données biologiques» programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the «fondazione Monzino». The authors thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr. Annalisa LoGerfo for her technical assistance in the DNA purification studies. Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundación Ramón Areces to the CBMSO. The authors thank I. Sastre and Dr. A. Martínez-García for the preparation and control of the DNA collection, and Drs. P. Gil and P. Coria for their cooperation in the cases/controls recruitment. The authors are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. CHARGE AGES: The AGES-Reykjavik Study is funded by National Institutes of Health (NIH) contract N01-AG-12100 (National Institute on Aging (NIA) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute (NHLBI)), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H. Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098, AG027058 and AG033193 (Seshadri) from the NIA. A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with A_ymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Drs. Seshadri and DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010. Fundació ACE would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). The authors thank to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission;and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01- HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01-HL096917 (Mosley) and R01-HL093029; NHGRI contract U01- HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research United Kingdom (ARUK) and the Welsh Government. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R & D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. The Homburg group was funded by the German Federal Ministry of Education and Research (BMBF): German National Genome Research Network (NGFN); Alzheimer's disease Integrated Genome Research Network; AD-IG: 01GS0465. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Harald Hampel was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. The authors acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Nottingham Group (KM) are supported by the Big Lottery. MRC CFAS is part of the consortium and data will be included in future analyses. ADGC The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, R01 AG041797; MIRAGE R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health

Published
2014
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13. Common variants at 12q14 and 12q24 are associated with hippocampal volume

Author

Bis, Joshua C, DeCarli, Charles, Schuur, Maaike, Grimm, Oliver, Hollinshead, Marisa, Holmes, Avram J, Homuth, Georg, Hottenga, Jouke-Jan, Langan, Camilla, Lopez, Lorna M, Hansell, Narelle K, Hwang, Kristy S, Kim, Sungeun, Yu, Lei, Laje, Gonzalo, Lee, Phil H, Liu, Xinmin, Loth, Eva, Lourdusamy, Anbarasu, Maniega, Susana Muñoz, Mattingsdal, Morten, Mohnke, Sebastian, Nho, Kwangsik, Nugent, Allison C, Choi, Seung-Hoan, O'Brien, Carol, Papmeyer, Martina, Pütz, Benno, Ramasamy, Adaikalavan, Rasmussen, Jerod, Rijpkema, Mark, Risacher, Shannon L, Roddey, J Cooper, Rose, Emma J, Ryten, Mina, Sigurdsson, Sigurdur, Shen, Li, Sprooten, Emma, Strengman, Eric, Teumer, Alexander, Trabzuni, Daniah, Turner, Jessica, van Eijk, Kristel, van Erp, Theo G M, van Tol, Marie-Jose, Wittfeld, Katharina, Verhaaren, Benjamin F J, Wolf, Christiane, Woudstra, Saskia, Aleman, Andre, Alhusaini, Saud, Almasy, Laura, Binder, Elisabeth B, Brohawn, David G, Cantor, Rita M, Carless, Melanie A, Corvin, Aiden, DeStefano, Anita L, Czisch, Michael, Curran, Joanne E, Davies, Gail, de Almeida, Marcio A A, Delanty, Norman, Depondt, Chantal, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fagerness, Jesen, Lambert, Jean-Charles, Fox, Peter T, Freimer, Nelson B, Gill, Michael, Göring, Harald H H, Hagler, Donald J, Hoehn, David, Holsboer, Florian, Hoogman, Martine, Hosten, Norbert, Jahanshad, Neda, Jack, Clifford R, Johnson, Matthew P, Kasperaviciute, Dalia, Kent, Jack W, Kochunov, Peter, Lancaster, Jack L, Lawrie, Stephen M, Liewald, David C, Mandl, René, Matarin, Mar, Mattheisen, Manuel, Struchalin, Maksim, Meisenzahl, Eva, Melle, Ingrid, Moses, Eric K, Mühleisen, Thomas W, Nauck, Matthias, Nöthen, Markus M, Olvera, Rene L, Pandolfo, Massimo, Pike, G Bruce, Puls, Ralf, Stankovich, Jim, Reinvang, Ivar, Rentería, Miguel E, Rietschel, Marcella, Roffman, Joshua L, Royle, Natalie A, Rujescu, Dan, Savitz, Jonathan, Schnack, Hugo G, Schnell, Knut, Seiferth, Nina, Smith, Albert Vernon, Ibrahim-Verbaas, Carla A, Smith, Colin, Steen, Vidar M, Valdés Hernández, Maria C, Van den Heuvel, Martijn, van der Wee, Nic J, Van Haren, Neeltje E M, Veltman, Joris A, Völzke, Henry, Walker, Robert, Westlye, Lars T, Fleischman, Debra, Whelan, Christopher D, Agartz, Ingrid, Boomsma, Dorret I, Cavalleri, Gianpiero L, Dale, Anders M, Djurovic, Srdjan, Drevets, Wayne C, Hagoort, Peter, Hall, Jeremy, Heinz, Andreas, Zijdenbos, Alex, Foroud, Tatiana M, Le Hellard, Stephanie, Macciardi, Fabio, Montgomery, Grant W, Poline, Jean Baptiste, Porteous, David J, Sisodiya, Sanjay M, Starr, John M, Sussmann, Jessika, den Heijer, Tom, Toga, Arthur W, Veltman, Dick J, Walter, Henrik, Weiner, Michael W, Andreassen, Ole A, Apostolova, Liana G, Bastin, Mark E, Blangero, John, Brunner, Han G, Buckner, Randy L, Mazoyer, Bernard, Cichon, Sven, Coppola, Giovanni, de Zubicaray, Greig I, Deary, Ian J, Donohoe, Gary, de Geus, Eco J C, Espeseth, Thomas, Fernández, Guillén, Glahn, David C, Grabe, Hans J, Coker, Laura H, Hardy, John, Hulshoff Pol, Hilleke E, Jenkinson, Mark, Kahn, René S, McDonald, Colm, McIntosh, Andrew M, McMahon, Francis J, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morris, Derek W, Enzinger, Christian, Müller-Myhsok, Bertram, Nichols, Thomas E, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W, Potkin, Steven G, Sämann, Philipp G, Saykin, Andrew J, Schumann, Gunter, Danoy, Patrick, Smoller, Jordan W, Wardlaw, Joanna M, Weale, Michael E, Martin, Nicholas G, Franke, Barbara, Wright, Margaret J, Thompson, Paul M, Amin, Najaf, Arfanakis, Konstantinos, van der Lijn, Fedde, van Buchem, Mark A, de Bruijn, Renée F A G, Beiser, Alexa, Dufouil, Carole, Huang, Juebin, Cavalieri, Margherita, Thomson, Russell, Niessen, Wiro J, Chibnik, Lori B, Gislason, Gauti K, Crivello, Fabrice, Hofman, Albert, Pikula, Aleksandra, Amouyel, Philippe, Freeman, Kevin B, Phan, Thanh G, Oostra, Ben A, Stein, Jason L, Medland, Sarah E, Vasquez, Alejandro Arias, Hibar, Derrek P, Fornage, Myriam, Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis, Nalls, Michael A, Uitterlinden, Andre G, Au, Rhoda, Elbaz, Alexis, Beare, Richard J, Debette, Stephanie, van Swieten, John C, Lopez, Oscar L, Harris, Tamara B, Chouraki, Vincent, Breteler, Monique M B, De Jager, Philip L, Becker, James T, Vernooij, Meike W, Knopman, David, Fazekas, Franz, Shulman, Joshua M, Wolf, Philip A, van der Lugt, Aad, Gudnason, Vilmundur, Longstreth, W. T., Brown, Matthew A, Bennett, David A, van Duijn, Cornelia M, Mosley, Thomas H, Schmidt, Reinhold, Tzourio, Christophe, Schmidt, Helena, Launer, Lenore J, Ikram, M Arfan, Seshadri, Sudha, Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Arias Vasquez, Alejandro, Senstad, Rudy E, Winkler, Anderson M, Srikanth, Velandai, Toro, Roberto, Appel, Katja, Bartecek, Richard, Bergmann, Ørjan, Bernard, Manon, Brown, Andrew A, Cannon, Dara M, Chakravarty, Mallar, Christoforou, Andrea, Domin, Martin, University of Washington [Seattle], University of California [Davis] (UC Davis), University of California, Center for Neuroscience, University of California-University of California, Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, The University of Texas Health Science Center at Houston (UTHealth), Human Genetics Center, Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France, Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institute of Molecular Biology and Biochemistry, Medical University Graz, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Rush University Medical Center [Chicago], Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Université Lille Nord de France (COMUE), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Radiology, Mayo Clinic, Biospective [Montréal], Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands, Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center, Department of Neurology, Medical University Graz, Graz, Austri, University of Queensland, Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia, Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, University of Mississippi Medical Center (UMMC), Delft University of Technology (TU Delft), Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Queensland Institute of Medical Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], National Institutes of Health [Bethesda] (NIH), Unité de recherche Neuroépidémiologie [CHU Pitié-Salpêtrière], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Murdoch Children's Research Institute (MCRI), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Harvard University [Cambridge], Harvard Medical School [Boston] (HMS), Mayo Clinic [Rochester], Human Genetics Group, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, University of Bordeaux, U708, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, University of California (UC), University of California (UC)-University of California (UC), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], Radboud University [Nijmegen], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard University, Other departments, Human genetics, EMGO - Mental health, NCA - Attention & Cognition, Radiology & Nuclear Medicine, Epidemiology, Neurology, Cardiothoracic Surgery, Clinical Genetics, Internal Medicine, Biological Psychology, Neuroscience Campus Amsterdam - Attention & Cognition, and EMGO+ - Mental Health

Subjects
Netherlands Twin Register (NTR), genetics [Alzheimer Disease], Genome-wide association study, DCN PAC - Perception action and control, genetics [Cognition Disorders], Hippocampal formation, Hippocampus, 0302 clinical medicine, Polymorphism (computer science), Cognitive decline, Genetics, 0303 health sciences, Translational research Immune Regulation [ONCOL 3], Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Alzheimer's disease, Genetic Markers, medicine.medical_specialty, DCN MP - Plasticity and memory, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, genetics [Dementia], Alzheimer Disease, ddc:570, Internal medicine, medicine, Humans, SNP, Chromosome 12, 030304 developmental biology, Chromosomes, Human, Pair 12, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Endocrinology, Genetic Loci, physiopathology [Hippocampus], Dementia, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 110608.pdf (Publisher’s version ) (Closed access) Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of

Published
2012
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14. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study.

Author

Seshadri, Sudha, DeStefano, Anita L., Au, Rhoda, Massaro, Joseph M., Beiser, Alexa S., Kelly-Hayes, Margaret, Kase, Carlos S., D'Agostino, Sr., Ralph B., DeCarli, Charles, Atwood, Larry D., and Wolf, Philip A.

Subjects
*MAGNETIC resonance imaging, *AGING, *BRAIN, *ALZHEIMER'S disease, *CEREBROVASCULAR disease, *DEMENTIA
Abstract

Background: Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genomewide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods: A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999-2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. Results: The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1). [ABSTRACT FROM AUTHOR]

Published
2007
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15. Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

Author

Debette, Stéphanie, Ibrahim Verbaas, Carla A., Bressler, Jan, Schuur, Maaike, Smith, Albert, Bis, Joshua C., Davies, Gail, Wolf, Christiane, Gudnason, Vilmundur, Chibnik, Lori B., Yang, Qiong, deStefano, Anita L., de Quervain, Dominique J.F., Srikanth, Velandai, Lahti, Jari, Grabe, Hans J., Smith, Jennifer A., Priebe, Lutz, Yu, Lei, and Karbalai, Nazanin

Subjects
*DISEASES in older people, *DEMENTIA research, *COGNITIVE ability, *AGING, *ALZHEIMER'S disease, *UBIQUITIN
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 × 10 −6 ) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. Results rs4420638, near APOE , was associated with poorer delayed recall performance in discovery ( p = 5.57 × 10 −10 ) and replication cohorts ( p = 5.65 × 10 −8 ). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [ HS3ST4 ] , p = 3.11 × 10 −8 , and rs6813517 [ SPOCK3 ], p = 2.58 × 10 −8 ) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5 , both related to ubiquitin metabolism. Conclusions This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways. [ABSTRACT FROM AUTHOR]

Published
2015
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