Extended Data Fig. 4: Results from genetic ancestry- and sex-specific burden analyses.
a, The numbers of epilepsy cases (orange) and controls (blue) by genetic ancestry. b, Comparison of protein-truncating (left) and damaging missense (right) URV burden in the top ten genes from the primary analysis (‘All’) across genetic ancestry subgroups. Red color indicates enrichment in cases (log[OR] > 1), with an asterisk indicating nominal significance (P≤ 0.05; see Supplementary Data 14 for exact P values). P values are computed using a Firth logistic regression model testing the association between the case-control status and the number of URVs (two-sided). c, Genetic ancestry-specific burden of URVs in established epilepsy genes (N = 171 curated by the Genetic Epilepsy Syndromes [GMS] panel with a known monogenic/X-linked cause), constrained genes (N = 1,917 scored by the loss-of-function observed/expected upper bound fraction [LOEUF] metric as the most constrained 10% genes), and constrained genes excluding established epilepsy genes (N = 1,813). Overall, different ancestral groups show at least partially shared burden of deleterious URVs in these gene sets. In a-c, NFE: Non-Finnish European (Ncase=16,040, Ncontrol = 25,641), AFR: African (Ncase=1,598, Ncontrol = 2,592), AMR: Ad Mixed American (Ncase=480, Ncontrol = 3,106), EAS: East Asian (Ncase=1,698, Ncontrol = 1,215), FIN: Finnish (Ncase=926, Ncontrol = 537), SAS: South Asian (Ncase=237, Ncontrol = 353). d, Sex-specific burden of URVs in established epilepsy genes. Burden analyses are performed for three gene sets described in c, with an additional set of 37 X-linked GMS epilepsy genes, across four epilepsy groups (female: NDEE = 811, NGGE = 4,807, NNAFE = 3,511, NEPI(all)=11,372, Ncontrol = 18,144; male: NDEE = 997, NGGE = 2,579, NNAFE = 4,395, NEPI(all)=10,397, Ncontrol = 15,302). There is an overall trend of shared URV burden between female and male subgroups in these gene sets. In c and d, the dot represents the log odds ratio and the error bars represent the 95% confidence intervals of the point estimates. For presentation purposes, error bars that exceed a large log odds ratio value are capped, indicated by arrows at the end of the error bars (see Supplementary Data 14 and 15 for exact values). e, Comparison of sex-specific burden of protein-truncating URVs at level of the individual genes. For each gene, the −log10-transformed P value from the female subgroup analysis (y-axis) is plotted against that from the male subgroup analysis (x-axis). Top ten genes with URV burden in epilepsy are labeled for each subgroup, with genes on the sex chromosomes colored in blue. The red dashed line indicates exome-wide significance P = 3.4 × 10−7 after Bonferroni correction.
