Manifestations of Alzheimer's disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90

Abstract

Genetics play an important role in late-onset Alzheimer's Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Figure 1

Statistically significant SNP-analyte associations after correcting for multiple testing (threshold FDR-adjusted p-value = 0.05), by SNP. Top panel: log-transformed beta-coefficient from the linear regression model adjusted for sex, age, and genetic principal components 1–4; markers above the zero line (orange) indicate analytes that increased in value with the minor allele, while markers below the line indicate markers that decreased in value. Second panel: FDR-adjusted − log₁₀ p-value; orange line at FDR-p = 0.05. Proteins = red, metabolites = blue, clinical chemistries = purple. Metabolite codes: DG diacylglycerol, LC lactosylceramide, o oleoyl; a arachidonoyl, g glycerol, l linoleoyl, p palmitoyl. Third panel: minor allele frequency (MAF). Bottom panel: Total sample size for each analyte-SNP regression.

Figure 2

Unadjusted box plots of normalized protein expression (NPX) levels of PILRA and PILRB by genotype and age group. White boxplots = individuals who are homozygous for the major allele, gray boxplots = heterozygotes, black boxplots = minor allele homozygotes. Box plot midline = median value, lower/upper hinges = 25th and 75th percentiles, respectively; lower whisker ends/upper whisker ends no further than 1.5× interquartile range from the hinge. Data beyond whiskers are outlying points. Top panel: NPX of PILRA and PILRB by rs12539172 (NYAP1) genotype; Bottom panel: NPX of PILRA and PILRB by rs1859788 genotype.

Figure 3

Unadjusted box plots of normalized protein expression levels (NPX) of six proteins significantly associated with APOE2 genotype, by age group. White boxplots = individuals who are homozygous for the major allele, gray boxplots = heterozygotes, black boxplots = minor allele homozygotes. Box plot midline = median value, lower/upper hinges = 25th and 75th percentiles, respectively; lower whisker ends/upper whisker ends no further than 1.5× interquartile range from the hinge. Data beyond whiskers are outlying points. LDLR low-density lipoprotein receptor, HMOX1 heme oxygenase-1, SLAMF8 SLAM family member 8, RNF31 E3 ubiquitin-protein ligase RNF31, CNTNAP2 contactin-associated protein-like 2, SRP14 signal recognition particle 14 kDa protein.

Figure 4

Heatmap of statistically significant genotype × sex interaction terms at FDR-adjusted p-value < 0.1. Beta coefficients obtained from sex-stratified analyses, middle-column p-values from interaction term in the full model. SL sphingolipid, LCFA long-chain fatty acid, PFA polyunsaturated fatty acid.