Figure 4. Representation of 46 genes spanning the 22q11.2 LCR22A-LCR22D deletion region annotated for contextual information and results from the current study:
Representation of 46 genes spanning the 22q11.2 low copy repeat (LCR) LCR22A-LCR22D deletion region annotated for contextual information and, on grey background, results from the current study. The sections numbered 1ā11 indicate the following:
1) Gene expression in brain, ranging from none to low (white) to low-medium (yellow) to medium-high (orange) to very high (red) according to BrainSpan (BrainSpan: Atlas of the Developing Human Brain [[http://developinghumanbrain.org]]http://developinghumanbrain.org]) and as previously processed by (10);
2 & 3) Exome Aggregation Consortium (ExAC) (48) calculated probability (ranging from 0 to 1.00, shown as a spectrum from white to deep violet) that the gene is intolerant to (2) two LOF variants (recessive; pRec), or (3) a single LOF variant (haploinsufficient; pLI);
4 & 5) Neuro-phenotype data availability, (4) from mouse in the form of mouse homologues from MGI (49) as a union of two MPO-based gene-sets [MP:0005386 behavior/neurological phenotype, MP:0003631 nervous system phenotype] as used in (10), and (5) for human neurologic disease genes from the Clinical Genomic Database (CGD) (CGD: Clinical Genomic Database. [https://research.nhgri.nih.gov/CGD/]);
6) Clusters of small rare deletions in the general population per the Database of Genomic Variants (DGV) (50), indicating presumed tolerance to hemizygosity, where an aqua circle/oval represents a single deletion cluster of ā¤1% frequency;
7) Rare LOF variants found in this 22q11.2DS cohort, thus representing a presumed null mutation, each variant observed in a single individual either within the schizophrenia (magenta) or non-psychotic (green) subgroups; number indicates the number of individuals (1, 2, or 3) in the schizophrenia or non-psychotic group with a LOF variant identified;
8) Genes in the 22q11.2 deletion region that show nominal significance for rare variants (in yellow, p-values ranged between 7.92E-03 and 4.75E-02 based on SKAT or Burden test) or for common variants (in red, p-values ranged between 3.63E-03 and 4.23E-02 based on SKAT test) in gene-based association tests for schizophrenia in this study using data for the subset of European ancestry. All results for the SKAT gene-based test for common variants can be found in Table S19. Note that all genes with nominal significance for rare variants are indicated in yellow, but that only CDC45, PI4KA, CLTCL1 and TRMT2A comply with the nā„5 rare variants criterion (see Table S15 for exact number of rare variants).
9) Schematic of gene positions in the 22q11.2 region.
10) Schematic of the positions, relative to genes, of the main 22q11.2 deletion region LCR22s A, B, C, and D.
11) Approximate genomic extents of the two most common 22q11.2 deletion sizes.
NA = Data not available.