rs242557

A study of 175 PSP (progressive supranuclear palsy) cases examining effects of GWAS-identified risk variants on brain gene expression, CpG methylation, and neuropathology. PSP risk SNPs rs8070723, rs242557, and rs1768208 were associated with altered brain levels of LRRC37A4, ARL17B, ARL17A, and MOBP. Meta-analysis confirmed highly significant associations for rs8070723 with LRRC37A4 and rs1768208 with MOBP. Risk alleles also associated with increased tau neuropathology including coiled bodies and tau threads, suggesting these variants influence PSP risk through effects on gene expression and tau pathology.

This dissertation study identified HLA region haplotypes associated with Alzheimer's disease risk using imputation and direct sequencing. In 11,690 combined UCSF and Alzheimer's Disease Genetics Consortium subjects, the five-allele haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 was associated with increased AD risk (OR=1.21, p=9.6×10⁻⁴). The DR15 haplotype (DRB1*15:01~DQA1*01:02~DQB1*06:02) was associated with faster cognitive decline and higher baseline inflammation. Direct sequencing confirmed these findings and revealed the six-allele haplotype A*03:01~B*07:02~C*07:02~DRB1*15:01~DQB1*06:02~DPB1*04:01 had a protective effect in atypical AD (OR=0.18, p=0.01) despite conferring risk in typical amnestic AD.

This large case-control study of 5,302 Parkinson's disease cases and 4,161 controls from 15 sites examined the independent and joint effects of SNCA and MAPT genes. Four SNCA SNPs (rs2583988, rs181489, rs356219, rs11931074) and two MAPT SNPs (rs1052553, rs242557) were all significantly associated with PD risk, with SNCA variants at the 3' end showing the strongest associations. Notably, no evidence of statistical interaction was found between SNCA and MAPT SNPs on either multiplicative or additive scales, despite their independent contributions to PD susceptibility.

This case-control association study in 4,124 Spanish Alzheimer's disease cases and 3,290 controls demonstrates that the MAPT H1 haplotype, tagged by rs1800547, is a risk factor for AD (OR=1.12, p=0.0025) primarily in APOE ε4 non-carriers (OR=1.15, p=0.0022). Pooled analysis of two Spanish datasets totaling 17,996 individuals shows strongest AD risk in the oldest APOE ε4 non-carriers, suggesting MAPT H1 variants may track a genuine risk allele through a tau-dependent pathway less dependent on amyloid burden.

A review of genetic discoveries in Alzheimer's disease using cerebrospinal fluid (CSF) levels of amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau181) as endophenotypes. The paper discusses multiple GWAS and sequencing studies that identified novel AD risk variants including rs9877502 (3q28, p=4.89×10⁻⁹), rs514716 in GLIS3 (p=1.07×10⁻⁸), and rs6922617 in TREM cluster (p=3.58×10⁻⁸), as well as functional characterization of known AD variants including APOE, MAPT, and TREM2. The review emphasizes the increased statistical power of using quantitative CSF biomarkers compared to traditional case-control designs.

This dissertation study identified HLA haplotypes associated with Alzheimer's disease risk using case-control imputation and direct sequencing. The haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 was associated with increased AD risk (p=9.6×10⁻⁴, OR=1.21 [1.08-1.37]) in 11,690 combined UCSF and ADGC participants, with effects primarily in APOE4 non-carriers. A separate haplotype showed decreased risk for atypical AD (p=0.01, OR=0.18). The findings highlight the role of immune-related genetic variation in AD pathophysiology.