Burden testing for rare deleterious variants in all genes across the MIS-C cohort . (A) Circularized Manhattan plot for the combined MIS-C cohort (n = 144; ⁿEUR = 4-; ⁿAFR = 41, ⁿAMR = 45, ⁿSAS = 18). The radial axis depicts the −log₁₀(P value) of the observed burden in MIS-C, while the angular axis is arranged by genomic coordinate clock-wise. Each point in the graph represents a gene, with its radius corresponding to the empirical burden P value and its angle corresponding to the gene’s chromosomal position. The exome-wide significance threshold is denoted by the dashed inner circle. 12 genes carry a statistically significant burden of rare deleterious variants, but 11 of them are only significant in one ancestral group. (B) Circularized Manhattan plot for all the constituent ancestral groups in our MIS-C cohort. Each ancestry is represented in concentric plots of increasing radius to facilitate comparisons. As denoted in red, the only gene that is independently significant in multiple ancestries is BTNL8. (C) Breakdown of findings by ancestry, demonstrating the empirical P value estimation for BTNL8. Control burden distributions are simulated for each population based on ancestry-specific AFs and the actual sample size of the corresponding ancestral group in the MIS-C cohort. The aggregated BTNL8 variants that are observed in MIS-C are then compared with the simulated burden distributions to determine the probability of observing a more extreme outcome. A combined P value for the entire cohort is obtained from the joint burden distribution across ancestries. BTNL8 is statistically significant in the EUR and AMR ancestral groups (as denoted by the blue tail of the distribution) and nominally significant (AF < 0.05) in AFR and SAS (as denoted by the red tail of the distribution). As a result, BTNL8 is also exome-wide significant in the combined analysis. (D) Effect size of BTNL8 association across three cohorts. ORs for each cohort are broken down by ancestry and also include a combined effect denoted by diamonds. The ORs are depicted in log scale, with values of 0 corresponding to no difference between cases and controls. In our MIS-C cohort, rare deleterious variants in BTNL8 appear to have a large effect, with a 4.2-fold increase in odds. This signal is largely driven by the EUR and AMR subpopulations, but all MIS-C ancestral groups have an OR > 2. In the comparator cohorts of COVID-HGE and EUCLIDS, BTNL8 appears to have no effect with ORs around 1 across ancestries. All variants considered have an allele frequency of <1% and CADD score >20.