Wang, Weixin

AbstractBackgroundGenetic risk in common variants have been identified for Progressive Supranuclear Palsy (PSP), but common variants only account for a portion of disease heritability. A proportion of the remaining disease heritability is likely contributed by rare variants identifiable via sequencing. Leveraging whole‐genome sequencing of 1719 PSP cases and 2940 controls from the Alzheimer’s Disease Sequencing Project, we detected single nucleotide variants (SNVs), insertion/deletions (INDELs), and copy number variants (CNVs). Note that all samples are non‐Hispanic whites with identity by descent (IBD) >0.25, and no outlier is >6 standard deviation in the principal component analysis. We conducted association analysis for variants, genes and gene sets to identify rare genetic risk for PSP.MethodAfter quality control (variants and genotypes notated PASS by the calling algorithms), we detected 85,228,234 rare SNVs/INDELs and 163,987 rare CNVs (minor allele frequency (MAF) < 1%). For rare SNVs/INDELs, the Sequence Kernel Association Test Optimized was performed to identify rare genetic PSP risk from protein truncating variants (PTV) and damaging missense variants (MAF<0.01%) in both protein coding genes and gene sets that were previously associated with PSP based on protein co‐expression networks. For rare CNVs, a permutation‐based association test implemented in Plink was performed to identify CNVs associated with PSP.ResultCombining protein truncating variants (PTV) and damaging missense variants, we identified one genome‐wide significant gene, FBXO38 (FDR = 0.0003, OR = 1.78). We also found enrichment of PTVs and damaging missense variants in genes comprising the C2 module, a neuronal module previously identified in post mortem PSP brain (FDR = 0.0016). For CNV analysis, there were 17 significant deletions and 2 significant duplications that were associated with PSP (Padjust < 0.05). The deletion (18:58488230‐58488489) in ALPK2, which has been identified as an Alzheimer’s Disease risk gene, was the only CNV that conferred a higher‐risk for PSP. Particularly, one deletion (17:46009357‐46009595) was in linkage disequilibrium with MAPT H2 haplotype which has been associated various neurodegenerative diseases including PSP.ConclusionWe identified several new genes and a protein co‐expression network in which risk variants were associated with PSP. These genes and pathways provide potential candidate drug targets for future investigation.

AbstractIntroductionAfrican‐American (AA) individuals have a higher risk for late‐onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.MethodsWe performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.ResultsCompared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.DiscussionExploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.