Browsing by Author "Gur, Raquel E."
Now showing 1 - 4 of 4
Results Per Page
Sort Options
Item Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects(2020) Zhao, Yingjie; Diacou, Alexander; Johnston, H. Richard; Musfee, Fadi I; McDonald-McGinn, Donna M.; McGinn, Daniel; Crowley, T. Blaine; Repetto, Gabriela; Swillen, Ann; Breckpot, Jeroen; Vermeesch, Joris R; Kates, Wendy R.; Digilio, M. Cristina; Unolt, Marta; Marino, Bruno; Pontillo, Maria; Armando, Marco; Di Fabio, Fabio; Vicari, Stefano; Bree, Marianne van den; Moss, Hayley; Owen, Michael J.; Murphy, Kieran C.; Murphy, Clodagh M.; Murphy, Declan; Schoch, Kelly; Shashi, Vandana; Tassone, Flora; Simon, Tony J.; Shprintzen, Robert J.; Campbell, Linda; Philip, Nicole; Heine-Suñer, Damian; García-Miñaúr, Sixto; Fernández, Luis; Bearden, Carrie E.; Vingerhoets, Claudia; Amelsvoort, Therese van; Eliez, Stephan; Schneider, Maude; Vorstman, Jacob A. S.; Gothelf, Doron; Zackai, Elaine; Agopian, A. J.; Gur, Raquel E.; Bassett, Anne S.; Emanuel, Beverly S.; Goldmuntz, Elizabeth; Mitchell, Laura E.; Wang, Tao; Morrow, Bernice E.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.Item 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, GabrielaSchizophrenia 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 presentItem Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness(2020) Ching, Christopher R.K.; Gutman, Boris A.; Sun, Daqiang; Villalon Reina, Julio; Ragothaman, Anjanibhargavi; Isaev, Dmitry; Zavaliangos-Petropulu, Artemis; Lin, Amy; Jonas, Rachel K.; Kushan, Leila; Pacheco-Hansen, Laura; Vajdi, Ariana; Forsyth, Jennifer K.; Jalbrzikowski, Maria; Bakker, Geor; Amelsvoort, Therese van; Antshel, Kevin M.; Fremont, Wanda; Kates, Wendy R.; Campbell, Linda E.; McCabe, Kathryn L.; Craig, Michael C.; Daly, Eileen; Gudbrandsen, Maria; Murphy, Clodagh M.; Murphy, Declan G.; Murphy, Kieran C.; Fiksinski, Ania; Koops, Sanne; Vorstman, Jacob; Crowley, Blaine; Emanuel, Beverly S.; Gur, Raquel E.; McDonald-McGinn, Donna M.; Roalf, David R.; Ruparel, Kosha; Schmitt, J. Eric; Zackaile, Elaine H.; Durdle, Courtney A.; Goodrich-Hunsaker, Naomi J.; Simon, Tony J.; Bassett, Anne S.; Butcher, Nancy J.; Chow, Eva W.C.; Vila-Rodriguez, Fidel; Cunningham, Adam; Doherty, Joanne; Linden, David E.; Moss, Hayley; Owen, Michael J.; Bree, Marianne van den; Crossley, Nicolas A.; Repetto, Gabriela; Thompson, Paul M.; Bearden, Carrie E.Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6–56 years; 49% female). Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen’s d values, 20.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen’s d values, 20.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.Item Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome(2020) Davies, Robert W.; Fiksinski, Ania M.; Breetvelt, Elemi J.; Williams, Nigel M.; Hooper, Stephen R.; Monfeuga, Thomas; Bassett, Anne S.; Owen, Michael J.; Gur, Raquel E.; Morrow, Bernice E.; McDonald-McGinn, Donna M.; Swillen, Ann; Chow, Eva W. C.; Bree, Marianne van den; Emanuel, Beverly S.; Vermeesch, Joris R.; Amelsvoort, Therese van; Arango, Celso; Armando, Marco; Campbell, Linda E.; Cubells, Joseph F.; Eliez, Stephan; Garcia-Minaur, Sixto; Gothelf, Doron; Kates, Wendy R.; Murphy, Kieran C.; Murphy, Clodagh M.; Murphy, Declan G.; Philip, Nicole; Repetto, Gabriela; Shashi, Vandana; Simon, Tony J.; Suñer, Damiàn Heine; Vicari, Stefano; Scherer, Stephen W.; Bearden, Carrie E.; Vorstman, Jacob A. S.; International 22q11.2 Brain and Behavior ConsortiumThe 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.