Browsing by Author "van den Bree, Marianne"

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    Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects
    (American Society of Human Genetics by Elsevier Inc., 2020-01) Zhao, Yingjie; Diacou, Alexander; Johnston, Richard; Musfee, Fadi; McDonald-McGinn, Donna; McGinn, Daniel; Crowley, Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris; Kates, Wendy; Digilio, Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; van den Bree, Marianne; Moss, Hayley; Owen, Michael; Murphy, Kieran; Murphy, Clodagh; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora
    The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10-5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.
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    Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
    (2020) Cleynen, Isabelle; Engchuan, Worrawat; Hestand, Matthew; Heung, Tracy; Holleman, Aarón M.; Johnston, Richard; Monfeuga, Thomas; McDonald McGinn, Donna M.; Gur, Raquel E.; Morrow, Bernice E.; Swillen, Ann; Vorstman, Jacob A. S; Bearden, Carrie E.; Chow, Eva W. C.; van den Bree, Marianne; Emanuel, Beverly S.; Vermeesch, Joris R.; Warren, Stephen T.; Owen, Michael J.; Chopra, Pankaj; Cutler, David J.; Duncan, Richard; Kotlar, Alex V.; Mulle, Jennifer G.; Voss, Anna J.; Zwick, Michael E.; Diacou, Alexander; Golden, Aaron; Guo, Tingwei; Lin, Jhih Rong; Wang, Tao; Zhang, Zhengdong; Zhao, Yingjie; Marshall, Marshall; Merico, Daniele; Jin, Andrea; Lilley, Brenna; Salmons, Harold I.; Oanh, Tran; Pardinas, Antonio; Repetto, Gabriela
    Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6 ). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present

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