Extended Data Fig. 5: Rare variant analyses.
a, Quantile-quantile (qq) plot of observed gene two-tailed −log10 (P-values) versus expected two-tailed −log10 (P-values) under the null model. Gene-based associations of low-frequency (MAF < 0.05) variants were estimated using the ACAT omnibus test including Firth’s logistic regression, SKAT and ACAT-V. Gene-based associations of ultra-rare variants (≤5 carriers) were estimated using Firth’s logistic regression. b, Gene-based analysis of ultra-rare (≤5 carriers) non-synonymous variants. The y-axis shows the gene-based associations (two-tailed −log10(P-value)) plotted against genomic coordinates on the x-axis (GRCh38). The dashed line indicates exome-wide significance (P = 2.74 × 10−6). c, Quantile-quantile (qq) plot of observed single variant two-tailed −log10 (P-values) versus expected two-tailed −log10 (P-values) under the null model. The red dotted line indicates the exome-wide significance threshold (P = 1.17 × 10−7). λ indicates the observed genomic inflation factor, λ1000 indicates the genomic inflation factor for an equivalent study of 1,000 cases and 1,000 controls. d, The y-axis shows the single variant associations estimated using Firth’s logistic regression (two-tailed −log10(P-value)) plotted against genomic coordinates on the x-axis (GRCh38). The dashed line indicates the exome-wide significance threshold (P = 1.17 × 10−7). e,f, Significant genes and single variants were screened for technical biases arising from different sequencing centers by testing for an association with sequencing center (n = 1,048 and n = 1,136) among PD cases. The y-axis shows the two-tailed −log10 (P-values) from this case-case analysis compared to the two-tailed −log10 (P-values) from the case-control analysis. Genes and single variants were excluded if Pcase-case ≤ Pcase-con. In both gene-based (e) and single-variant analyses (f), technical bias was observed in the C5 gene. This was caused by one variant (C5; c.3127 C > A), of which all 44 carriers were sequenced in the same sequencing center.
