Fig. 3. New associations identified between PIK3R5, LZTS1 and COL4A1 and Braak NFT stage, arteriolosclerosis and cerebral atherosclerosis, respectively.

a, Braak stage association plot from NPE GWAS meta-analysis (n = 7,776) for the region around PIK3R5. Colored dots represent the chromosomal position (x axis, Mb) in hg38 coordinates and −log₁₀(P value from meta-analysis two-sided z test; y axis) of each variant in the region. Dots are colored to represent the LD r² with the lead variant (purple diamond) estimated with PLINK–r2 using 1000 Genomes phase 3 European-descended participants. The recombination rate was calculated using GRCh38 genetic map files downloaded from https://bochet.gcc.biostat.washington.edu/beagle/genetic_maps/ and taking the ratio of difference of CM and Mb between positions. Boxes below data indicate the location of genes in the region. (Plot generated using LocusZoom⁷³.) b, Association of PIK3R5 lead variant (rs72844606) with Braak stage for individual cohorts (NACC, n = 5,927; ROSMAP, n = 1,172 and ACT, n = 677) and meta-analysis (n = 7,776) using METAL (y axis). Points along the x axis represent OR of association, and error bars indicate 95% CI. c, Human brain cell-type expression profile of PIK3R5 in ref. ³⁵. Columns represent mean FPKM. Error bars indicate the s.e. of measurement for each cell type based on the number of human samples sequenced for each type (fetal astrocytes, n = 6; mature astrocytes, n = 12; endothelial, n = 2; microglia, n = 3; neurons, n = 1 and oligodendrocytes, n = 5). PIK3R5 is primarily expressed in microglia. d, Arteriolosclerosis association plot from NPE GWAS meta-analysis (n = 6,668) for the region around LZTS1 (see a for interpretation). e, Association of LZTS1 lead variant (rs78909048) with arteriolosclerosis for individual cohorts (NACC, n = 4,930; ROSMAP, n = 1,163 and ACT, n = 575) and meta-analysis (n = 6,668) using METAL (y axis; see b for interpretation). f, Human brain cell-type expression profile of LZTS1 in ref. ³⁵. LZTS1 is primarily expressed in fetal astrocytes and endothelial cells (see c for interpretation). g, Cerebral atherosclerosis association plot from NPE GWAS meta-analysis (n = 7,340) for the region around COL4A1 (see a for interpretation). h, Association of COL4A1 lead variant (rs2000660) with cerebral atherosclerosis for individual cohorts (NACC, n = 5,496; ROSMAP, n = 1,175 and ACT, n = 669) and meta-analysis (n = 7,340) using METAL (y axis; see b for interpretation). i, Human brain cell-type expression profile of COL4A1 in ref. ³⁵. COL4A1 is preferentially expressed in fetal astrocytes and endothelial cells with lower expression in neurons (see c for interpretation). Mb, megabase.