Abstract
To elucidate how variants in genetic risk loci previously implicated in Alzheimer’s Disease (AD) and/or frontotemporal dementia (FTD) contribute to expression of disease phenotypes, a phenome-wide association study was performed in two waves. In the first wave, we explored clinical traits associated with thirteen genetic variants previously reported to be linked to disease risk using both the 23andMe and UKB cohorts. We tested 30 additional AD variants in UKB cohort only in the second wave. APOE variants defining ε2/ε3/ε4 alleles and rs646776 were identified to be significantly associated with metabolic/cardiovascular and longevity traits. APOE variants were also significantly associated with neurological traits. ABI3 variant rs28394864 was significantly associated with cardiovascular (e.g. (hypertension, ischemic heart disease, coronary atherosclerosis, angina) and immune-related trait asthma. Both APOE variants and CLU variant were significantly associated with nearsightedness. HLA- DRB1 variant was associated with diseases with immune-related traits. Additionally, variants from 10+ AD genes (BZRAP1-AS1, ADAMTS4, ADAM10, APH1B, SCIMP, ABI3, SPPL2A, ZNF232, GRN, CD2AP, and CD33) were associated with hematological measurements such as white blood cell (leukocyte) count, monocyte count, neutrophill count, platelet count, and/or mean platelet (thrombocyte) volume (an autoimmune disease biomarker). Many of these genes are expressed specifically in microglia. The associations of ABI3 variant with cardiovascular and immune-related traits are one of the novel findings from this study. Taken together, it is evidenced that at least some AD and FTD variants are associated with multiple clinical phenotypes and not just dementia. These findings were discussed in the context of causal relationship versus pleiotropy via Mendelian randomization analysis.
Highlights
Genome Wide Association Study (GWAS) is a powerful approach in identifying genetic risk loci
The directionality of association is consistent with the protective vs. risk effect of two Apolipoprotein E (APOE) single-nucleotide polymorphisms (SNPs) in that the minor allele of rs7412 was associated with lower risk of high cholesterol, while the minor allele of rs429358 was associated with higher risk of high cholesterol (p = 6.6 x 10−295)
Among the significant phenome-wide association studies (PheWAS) traits associated with the Alzheimer’s disease (AD)/Frontotemporal dementia (FTD) disease variants, a set of genetic variant instruments from Mendelian randomization (MR) Base for Body mass index (BMI) [54, 55], T2DM [56,57,58], lipid traits including HDL cholesterol, LDL cholesterol, and total cholesterol [59], CAD [60, 61], extreme height [55], parental attained age [62], traits defined from UK Biobank such as “reason for glasses/ contact lenses: For short-sightedness i.e. only or mainly for distance viewing such as driving, cinema, etc.”, and “non-cancer illness code self-reported: angina” analyses by PheWAS of AD/FTD loci and causal inference of significant PheWAS traits the Neale Lab v1), RA [63], Inflammatory bowel disease (UC and Crohn’s disease (CD)) [64, 65], CeD [66], multiple sclerosis (MS) [67, 68] were obtained
Summary
Genome Wide Association Study (GWAS) is a powerful approach in identifying genetic risk loci. Meta-analysis of 74,046 individuals by International Genomics of Alzheimer’s Project (I-GAP) revealed 19 GWAS significant AD loci including 11 novel loci [21] These genes were implicated in cholesterol metabolism (APOE, CLU, and ABCA7), immune response (CR1, CD33, CLU, ABCA7), and endocytosis (BIN1, PICALM, CD2AP) [22]. In addition to the well-known AD and FTD genes, we have previously identified two genome wide significant variants associated with CSF Aβ42 levels [27] using Alzheimer’s Disease Neuroimaging Initiative (ADNI) samples. To elicit additional insight on these 13 SNPs previously implicated in AD and FTD, phenome-wide association studies (PheWAS) were performed using the database from the personal genetics company 23andMe, Inc. to identify phenotypes (both dementia and nondementia traits) associated with these variants of interest. Recent development of using genetic variants as an instrument variable in GWAS summary statistics based Mendelian randomization (MR) [37] provides another means to dissect the pleiotropy vs. causal relationship between related traits
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
