PMC:4067558 / 23933-26298 JSONTXT

{"project":"2_test","denotations":[{"id":"24768552-21170055-2047128","span":{"begin":200,"end":202},"obj":"21170055"},{"id":"24768552-18950739-2047129","span":{"begin":248,"end":250},"obj":"18950739"},{"id":"24768552-15642099-2047129","span":{"begin":248,"end":250},"obj":"15642099"},{"id":"24768552-20976243-2047130","span":{"begin":273,"end":275},"obj":"20976243"},{"id":"24768552-21784246-2047131","span":{"begin":293,"end":295},"obj":"21784246"},{"id":"24768552-22542183-2047132","span":{"begin":370,"end":371},"obj":"22542183"},{"id":"24768552-18059269-2047133","span":{"begin":2202,"end":2204},"obj":"18059269"}],"text":"FMRP Targets, PSD Genes, and Other Neuronal Genes Are Implicated in ASD\nWe expanded our analysis to lists of genes important for neurological function, such as highly-brain-expressed genes, PSD genes,33 genes implicated in neurological diseases,44,45 genes with a high pHI,35 and FMRP targets,34 the latter of which have been reported to be enriched in de novo LoF SNVs.7 Our analysis focused on exonic events, and deletions and duplications were analyzed separately (Figures 3A and 3B).\nFMRP targets (n = 842) and PSD genes (n = 1,453) carried a significant excess of both deletions and duplications in affected subjects (Figures 3A and 3B). Five percent (73/1,486) of affected subjects with exonic CNVs, including 52 subjects with genes not previously implicated in ASD and/or ID, carried deletions overlapping one or more FMRP targets, yielding 43 ASD candidate genes (Figure 3A; Table S10). Given that the lists of FMRP targets and PSD genes shared 279 genes, we performed conditional analyses showing that the excess of affected subjects carrying deletions overlapping PSD genes was independent of the signal in FMRP targets (OR = 2.62, 95% CI = 1.62–4.32, p = 2.24 × 10−5) and represented 4% of subjects with exonic events (59/1,486) or 3% after exclusion of pathogenic events (p = 0.007). Notably, females were overrepresented among affected subjects carrying exonic deletions overlapping FMRP targets (17 females in 73 affected subjects, 1.98-fold more than males, p = 0.022, 95% CI = 1.06–3.52).\nBrain-expressed genes showed significant excess in affected versus control subjects for deletions only (OR = 1.89, 95% CI = 1.51–2.37, Fisher’s exact test p = 2.6 × 10−8; Figures 3A and 3B). Similarly, deletions (and not duplications) overlapping genes implicated in dominant neurological diseases and orthologous genes associated with abnormal phenotypes in heterozygous knockout mice conferred significant increase in ASD risk (OR = 2.94, 95% CI = 1.76–4.93, p = 2.5 × 10−5). Many of the genes implicated in dominant diseases have been related to loss of function or haploinsufficiency, previously suggested to be more frequent and penetrant when deletions rather than duplications are involved.46 Accordingly, we detected an excess of affected subjects carrying deletions overlapping genes with a high pHI (\u003e0.35) (OR = 1.41, 95% CI = 1.13–1.76, p = 0.002)."}