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Non‐Coding Variants in MYH11, FZD3, and SORCS3 Are Associated

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Non‐Coding Variants in MYH11, FZD3, and SORCS3 Are Associated Received: 2 March 2020 Revised: 17 July 2020 Accepted: 3 August 2020 DOI: 10.1002/alz.12181 FEATURED ARTICLE Non-coding variants in MYH11, FZD3,andSORCS3 are associated with dementia in women 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 Correspondence Elizabeth E. Blue, Division of Medical Genet- Abstract ics, University of Washington, BOX 357220, Seattle WA 98195-7720. Introduction: Recent studies suggest that both sex-specific genetic risk factors and Email: [email protected] those shared between dementia and stroke are involved in dementia pathogenesis. Methods: We performed both single-variant and gene-based genome-wide associa- tion 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 associ- ation 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,andGOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3,andGOLGA8B, were differ- entially expressed in the context of Alzheimer’s disease. Discussion: Our association of MYH11, FZD3, SORCS3,andGOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia. KEYWORDS dementia, sex-specific, stroke, whole-genome sequence, women Alzheimer’s Dement. 2021;17:215–225. wileyonlinelibrary.com/journal/alz © 2020 the Alzheimer’s Association 215 216 BLUE ET AL. 1 BACKGROUND RESEARCH IN CONTEXT Over 20 years ago, the apolipoprotein E (APOE) ε4 allele was identi- 1. Systematic review: The authors performed a literature fied as a major genetic risk factor for late-onset Alzheimer’s disease review encompassing pre-prints and published articles (AD) and dementia.1,2 Genome-wide association studies (GWAS) have and abstracts investigating the relationship between identified >30 additional loci contributing to AD risk, with several stroke, sex, and dementia. Previous studies provided evi- more identified by exome-based studies.3 A substantial proportion of dence for shared risk factors between stroke and demen- dementia risk remains unexplained. This may be because GWAS are tia, and inconsistent evidence for sex-specific effects on typically underpowered for detecting associations with rare variants. dementia risk. Dementia also exhibits considerable phenotypic heterogeneity, and it 2. Interpretation: Genome scans revealed significant is often difficult to distinguishing AD from vascular or other subtypes associations between genetic variation in APOE, FZD3, of dementia.4–6 GOLGA8B, MYH11,andSORCS3 and dementia risk. There is a complex relationship between vascular risk factors Excluding the well-established apolipoprotein (APOE) and dementia. Both AD and cerebrovascular disease increase in locus, these loci have not been widely associated with prevalence with age and share risk factors like hypertension, APOE Alzheimer’s disease (AD) risk, but they have been asso- genotype, smoking, and diabetes mellitus.6 Stroke and dementia are ciated with cognitive traits, shared risk factors for each risk factors for the other, and there is accumulating evidence that dementia and stroke, and/or differential gene expres- they share susceptibility genes and pathways.7 There may also be sex- sion in the brain between AD cases and controls. They specific or hormonal differences that influence genetic susceptibility also find evidence for an interaction between hormone to AD or dementia.8 therapy, FZD3 genotype, and dementia risk. This analysis of >11,000 postmenopausal women from the 3. Future directions: Further studies across diverse popula- Women’s Health Initiative (WHI) study enriched for vascular disease tions, stratified by sex, and enriched for known risk fac- aims to discover new genetic loci associated with dementia. Our anal- tors for dementia may reveal new genetic pathways influ- ysis of whole genome sequence (WGS) data assesses variation across encing dementia. the allele frequency spectrum, including both coding and non-coding variants. We find strong association between dementia and APOE, as well as novel loci involving MYH11, FZD3, SORCS3,andGOLGA8B. Independent transcriptomic studies reveal that these loci are also associated with gene expression in the brain and that some of those [DP] = 39) and rs429358 (DP = 40). In total 1608 cases of dementia genes are differentially expressed in AD and dementia. were identified by self-report, medical history updates, and/or death certificate information (Supplemental Methods). Comparisons with dementia status adjudicated by an expert panel suggest that the clas- 2 METHODS sification of dementia in this sample has high specificity, but likely under-reports the true number of dementia cases. Although the major- 2.1 The women’s health initiative ity of dementia cases in the United States are affected by AD (60%- 80%), cerebrovascular disease, Lewy body disease, and frontotemporal The WHI is a prospective study of postmenopausal women represent- dementia (FTD); each represent the cause of dementia in 5% to 10% of ing a socio-demographically diverse population, recruiting 161,808 cases and up to 50% of dementia cases show mixed pathology.11 women between 1993 and 1998 (Supplemental Methods).9 The WHI included an Observational Study (WHI-OS) and randomized Clinical Trials (WHI-CT), including Hormone Therapy Trials (HT). Both the 2.2 Statistical analyses WHI-CT and WHI-OS cohorts have been actively followed for >25 years. WGS data were collected for 11,085 WHI participants through Single-variant association testing between dementia and single the Trans-Omics for Precision Medicine (TOPMed) project sponsored nucleotide variants (SNVs) and short insertions/deletions was by the National Heart, Lung and Blood Institute using a centralized, rig- performed using Scalable and Accurate Implementation of Gen- orous approach (https://www.nhlbiwgs.org/topmed-whole-genome- eralized mixed model (SAIGE)12 implemented in Encore (https:// sequencing-methods-freeze-8). Freeze 8 of the TOPMed data were encore.sph.umich.edu/), controlling type 1 error by adjusting for relat- aligned to the GRCh38 human reference and cleaned as previously edness and sample size imbalances (Supplemental Methods). Tests described (Supplemental Methods).10 were restricted to variants with minor allele frequency (MAF) >0.1% The WHI TOPMed participants included all eligible and consenting (N = 877,506,482). Covariates included age at enrollment, self- women with incident stroke (N = 4852) or venous thromboembolism reported ethnicity, stroke and VTE status, assignment in WHI-CT (VTE; N = 1162), women with coronary heart disease (CHD; N = 1797), versus WHI-OS, randomization arm for those in the HT trial, and and 4216 controls matched on age and ethnicity. APOE ε2/ε3/ε4 geno- principal components (PCs) 1-10 to control for population stratifi- types were defined using WGS genotypes at rs7412 (avg. read depth cation. Genome-wide significance was defined as P < 5 × 10−8,and BLUE ET AL. 217 lead variants as those with the smallest P value at a locus significantly to see evidence for differential gene expression between AD cases associated with dementia. For any loci with novel associations, we and controls in the appropriate tissues or cells. Lead variants from performed sensitivity analyses stratified by stroke status, APOE status, our GWAS were extracted from AD-specific eQTL studies to nominate history of HT at baseline, and reported ancestry. genes whose expression they may influence. We then determined Aggregation tests improve the statistical power to identify associa- if these genes were differentially expressed between those with tions driven by rare variants and can aid interpretation when variants and without dementia or AD within several recent studies of gene are aggregated by biological features like genes. We applied the opti- expression. mal unified sequence kernal association test (SKAT-O)13 which allows Evidence for eQTLs was collected from an Accelerating Med- for different variants within the same gene to have opposing effects. ical Partnerships for Alzheimer’s Disease (AMP-AD) consortium For variants with MAF ≤5%, we performed gene-based testing
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