Citations 12
Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Armstrong, Nicola J. , Mather, Karen A. , Sargurupremraj, Muralidharan , Knol, Maria J. , Malik, Rainer, Satizábal, Claudia L. , Yanek, Lisa R., Wen, Wei , Guðnason, Vilmundur , Dueker, Nicole , Elliott, Lloyd T. , Hofer, Edith, Bis, Joshua C. , Jahanshad, Neda , Li, Shuo , Logue, Mark, Scholz, Markus , Smith, Albert V. , Trompet, Stella , Alfaro‐Almagro, Fidel , Ames, David, Amin, Najaf , Beiser, Alexa S., Brodaty, Henry , Fennema‐Notestine, Christine , Gampawar, Piyush , Gottesman, Rebecca, Griffanti, Ludovica , Kral, Brian G. , Lampe, Leonie, Liewald, David C. , Maillard, Pauline , Marchini, Jonathan, Bastin, Mark E., Pirpamer, Lukas , Roshchupkin, Gennady V. , Stott, David J., Thalamuthu, Anbupalam , Tzourio, Christophe , Grond, Jeroen van der , Vernooij, Meike W. , Witte, A. Veronica , Wright, Margaret J. , Yang, Qiong, Siggurdsson, Siggi, Psaty, Bruce M., Villringer, Arno , Schmidt, Helena, Duijn, Cornelia M. van , Jukema, J. Wouter , Dichgans, Martin , Sacco, Ralph L., Kremen, William S., Becker, Lewis C. , Thompson, Paul M., Mosley, Thomas H. , Wardlaw, Joanna M. , Ikram, M. Arfan , Adams, Hieab H.H. , Seshadri, Sudha , Sachdev, Perminder S. , Smith, Stephen M. , Launer, L. J., Longstreth, W.T. , DeCarli, Charles , Schmidt, Reinhold, Fornage, Myriam , Debette, Stéphanie , DeCarli, Charles , Dichgans, Martin , Wardlaw, Joanna Marguerite , Thalamuthu, Anbupalam , Wen, Wei , Adams, Hieab H H , Satizabal, Claudia L , Seshadri, Sudha , Brodaty, Henry , Sachdev, Perminder S , Wright, Margaret J , Tzourio, Christophe , van Duijn, Cornelia M , Debette, Stephanie , Smith, Albert V , Maillard, Pauline , Hofer, Edith , Luciano, Michelle , Vojinović, Dina , Xia, Rui , Amouyel, Philippe , Deary, Ian J. , Jack, Clifford R. , Jenkinson, Mark , Jiang, Jiyang , Kwok, John B. , Marchini, Jonathan , Mazoyer, Bernard , Romero, José R. , Schofield, Peter R. , Schroeter, Matthias L , Trollor, Julian N , Morris, Zoë , Psaty, Bruce M. , Håberg, Asta K , Wright, Clinton B. , Thompson, Paul M. , Nyquist, Paul
Stroke | June 10, 2020 | Volume: 51 | Issue: 7 | Pages: 2111-2121
Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
THE RELATIONSHIP OF APOE ε4 TO THE RELATIVE TIMES AND HAZARDS OF DEMENTIA
Powell, Danielle, Kuo, Pei‐Lun, Gottesman, Rebecca, Palta, Priya, Gross, Alden L. , Deal, Jennifer A. , Knopman, David S.
Innovation in Aging | November 9, 2019 | Volume: 3 | Issue: Supplement_1 | Pages: S587-S587
Abstract Although APOE ε4 is an established risk factor for dementia, it is unclear whether it is associated with elevated risk or earlier symptom onset. Longitudinal study of 10,400 white-race individuals in the ARIC cohort followed from age 60 to incident dementia diagnosis, death, or censoring. All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive change, proxy report, and hospital or death certificate dementia codes. Death was ascertained via the National Death Index and death certificates. We used a parametric mixture of generalized gamma distributions to simultaneously estimate the distribution of event times and the proportion of individuals who experience each outcome (i.e., dementia and its competing risk, dementia-free death) by APOE ε4 status (≥ 1 allele vs. no alleles). Age-adjustment was through use of age as the time scale. APOE ε4 carrier status was associated with a doubling of the overall frequency of dementia incidence to 25% compared to 13% (p < 0.001) in non- ε4 carriers. The distributions of time to dementia was modified by APOE ε4 status (p=0.007): median time to dementia onset among APOE ε4 carriers was 81.9 years compared to 83.3 years in non-APOE ε4 carriers (p = 0.005). No differences in results were found by sex. APOE ε4 carrier status is associated with both elevated risk and earlier time to dementia onset. These findings clarify the causal role of APOE in dementia etiology, could help better identify at-risk subgroups, and may help facilitate better research recruitment.