Bioinformatique

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P 5 0.007) and evidence of replication in large independent European schizophrenia (P 5 0.052) and UK bipolar disorder case-control cohorts (P 5 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran -Mantel -Haenszel P-value 5 2 3 10 24 ; odds ratio (OR) 5 11.3, 95% CI 5 3.7, 1]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ∼149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P 5 2.5 3 10 221 ), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Hematological traits are important clinical parameters. To test the role of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin, hematocrit, white blood cell (WBC) and platelet count in 31,340 individuals genotyped on an exome array. We identified several missense variants of CXCR2 associated with reduced WBC count (gene-based P=2.6×10 −13 ). In a separate family-based re-sequencing study, we identified a novel loss-offunction CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified novel missense or splice site variants in key hematopoiesis regulators (EPO, TRF2, HBB, TUBB1, SH2B3) associated with blood cell traits. Finally, we were able to detect associations between the rare somatic JAK2 p.Val617Phe mutation and platelet count (P=3.9×10 −22 ) as well as hemoglobin (P=0.002), hematocrit (P=9.5×10 −7 ) and WBC (P=3.1×10 −5 ). In conclusion, exome arrays complement GWAS in identifying new variants that contribute to complex human traits.

Chromosomal translocations involving KMT2A gene are one of the most common genetic alterations found in pediatric acute myeloid leukemias (AML) although the molecular mechanisms that initiate the disease remain incompletely defined. To elucidate these initiating events we have used a human model system of AML driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin accessibility at each stage of our model system and correlated these with expression changes. We observe the development of a profound hypomethylation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem cell associated genes along with skewed expression in other genes such as S100A8/9 implicated in leukemogenesis. In addition, early increases in the expression of the lysine demethylase KDM4B was functionally linked to these expression changes as well as other key transcription fa...