Exome sequencing was performed on 222 OCD parent-child trios. WES data from 855 unaffected trios, already sequenced from the Simons Simplex Collection, were pooled with our OCD trios for joint variant calling. After quality control methods, our sample size for a burden analysis was 184 OCD and 777 unaffected trios (Figure 1, Table 1, Table S1). To compare the de novo and inherited mutation rates between cases and controls, we limited our analysis to loci with at least 20x coverage in all members of a trio, as this was our pre-defined threshold for calling a variant (see Methods). Based on our OCD pilot study (31) and work in other neurodevelopmental disorders (22, 24, 26, 28, 43), we expected to find an enrichment of de novo LGD variants (stop codon, frameshift, or canonical splice-site variants) in OCD probands versus controls. We found a statistically significant increased rate of de novo LGD variants in OCD cases, confirming our hypothesis (rate ratio [RR] 1.93, 95% Confidence Interval [CI] 1.19–3.09, p=0.01). Furthermore, de novo missense variants predicted to be damaging by PolyPhen2 (Mis-D; Polyphen2
