Elizabeth E Blue1, Timothy A Thornton2, Charles Kooperberg3, Simin Liu4,5,6, Jean Wactawski-Wende7, JoAnn Manson8, Lew Kuller9, Kathleen Hayden10, Alexander P Reiner3,11. 1. Division of Medical Genetics, University of Washington, Seattle, Washington, USA. 2. Department of Biostatistics, University of Washington, Seattle, Washington, USA. 3. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 4. Department of Epidemiology, Brown University, Providence, Rhode Island, USA. 5. Department of Surgery, Brown University, Providence, Rhode Island, USA. 6. Department of Medicine, Brown University, Providence, Rhode Island, USA. 7. Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York, USA. 8. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 9. Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 10. Department of Social Science and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 11. Department of Epidemiology, University of Washington, Seattle, Washington, USA.
Abstract
INTRODUCTION: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis. METHODS: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus. RESULTS: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease. DISCUSSION: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.
INTRODUCTION: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis. METHODS: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus. RESULTS: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease. DISCUSSION: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.
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