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2. A normative chart for cognitive development in a genetically selected population

Author

Fiksinski, Ania M, Bearden, Carrie E, Bassett, Anne S, Kahn, René S, Zinkstok, Janneke R, Hooper, Stephen R, Tempelaar, Wanda, McDonald-McGinn, Donna, Swillen, Ann, Emanuel, Beverly, Morrow, Bernice, Gur, Raquel, Chow, Eva, van den Bree, Marianne, Vermeesch, Joris, Warren, Stephen, Owen, Michael, van Amelsvoort, Therese, Eliez, Stephan, Gothelf, Doron, Arango, Celso, Kates, Wendy, Simon, Tony, Murphy, Kieran, Repetto, Gabriela, Suner, Damian Heine, Vicari, Stefano, Cubells, Joseph, Armando, Marco, Philip, Nicole, Campbell, Linda, Garcia-Minaur, Sixto, Schneider, Maude, Shashi, Vandana, Vorstman, Jacob, and Breetvelt, Elemi J

Subjects
Brain Disorders, Serious Mental Illness, Pediatric, Mental Health, Schizophrenia, Clinical Research, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adult, Cognition, DiGeorge Syndrome, Humans, Intelligence Tests, 22q11DS International Consortium on Brain and Behavior, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p

Published
2022

3. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Author

Cleynen, Isabelle, Engchuan, Worrawat, Hestand, Matthew S, Heung, Tracy, Holleman, Aaron M, Johnston, H Richard, Monfeuga, Thomas, McDonald-McGinn, Donna M, Gur, Raquel E, Morrow, Bernice E, Swillen, Ann, Vorstman, Jacob AS, Bearden, Carrie E, Chow, Eva WC, 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, Christian, Merico, Daniele, Jin, Andrea, Lilley, Brenna, Salmons, Harold I, Tran, Oanh, Holmans, Peter, Pardinas, Antonio, Walters, James TR, Demaerel, Wolfram, Boot, Erik, Butcher, Nancy J, Costain, Gregory A, Lowther, Chelsea, Evers, Rens, van Amelsvoort, Therese AMJ, van Duin, Esther, Vingerhoets, Claudia, Breckpot, Jeroen, Devriendt, Koen, Vergaelen, Elfi, Vogels, Annick, Crowley, T Blaine, McGinn, Daniel E, Moss, Edward M, Sharkus, Robert J, Unolt, Marta, Zackai, Elaine H, Calkins, Monica E, Gallagher, Robert S, Gur, Ruben C, Tang, Sunny X, Fritsch, Rosemarie, Ornstein, Claudia, Repetto, Gabriela M, Breetvelt, Elemi, Duijff, Sasja N, Fiksinski, Ania, Moss, Hayley, Niarchou, Maria, Murphy, Kieran C, Prasad, Sarah E, Daly, Eileen M, Gudbrandsen, Maria, Murphy, Clodagh M, Murphy, Declan G, Buzzanca, Antonio, Fabio, Fabio Di, Digilio, Maria C, Pontillo, Maria, Marino, Bruno, Vicari, Stefano, Coleman, Karlene, Cubells, Joseph F, Ousley, Opal Y, Carmel, Miri, Gothelf, Doron, Mekori-Domachevsky, Ehud, Michaelovsky, Elena, Weinberger, Ronnie, Weizman, Abraham, Kushan, Leila, Jalbrzikowski, Maria, Armando, Marco, Eliez, Stéphan, Sandini, Corrado, and Schneider, Maude

Subjects
International 22q11.2DS Brain and Behavior Consortium, Prevention, Serious Mental Illness, Genetics, Human Genome, Schizophrenia, Neurosciences, Mental Health, Clinical Research, Pediatric, Brain Disorders, 2.1 Biological and endogenous factors, Mental health, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

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.

Published
2021

4. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Author

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 WC, van den Bree, Marianne, Emanuel, Beverly S, Vermeesch, Joris R, van Amelsvoort, Therese, 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 M, Shashi, Vandana, Simon, Tony J, Suñer, Damiàn Heine, Vicari, Stefano, Scherer, Stephen W, Bearden, Carrie E, and Vorstman, Jacob AS

Subjects
Biomedical and Clinical Sciences, Health Sciences, Genetics, Schizophrenia, Serious Mental Illness, Behavioral and Social Science, Prevention, Brain Disorders, Clinical Research, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Adult, Aged, Child, Child, Preschool, Cognitive Dysfunction, Cohort Studies, DiGeorge Syndrome, Female, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Risk Factors, Young Adult, International 22q11.2 Brain and Behavior Consortium, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

The 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.

Published
2020

5. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

Author

Zhao, Yingjie, Diacou, Alexander, Johnston, H Richard, Musfee, Fadi I, McDonald-McGinn, Donna M, McGinn, Daniel, Crowley, T Blaine, Repetto, Gabriela M, 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, van den Bree, Marianne, 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, Consortium, International 22q11 2 Brain and Behavior, Antonarakis, Stylianos E, Biondi, Massimo, Boot, Erik, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Buzzanca, Antonino, Carmel, Miri, Cleynen, Isabelle, Cutler, David, Dallapiccola, Bruno, de la Fuente Sanches, María Angeles, Epstein, Michael P, Evers, Rens, Fernandez, Luis, Fritsch, Rosemarie, Algas, Fernando García, Guo, Tingwei, Gur, Raquel, Hestand, Matthew S, Heung, Tracy, Hooper, Stephen, Jin, Andrea, Kushan-Wells, Leila, Laorden-Nieto, Alejandra Teresa, Lattanzi, Guido, Marshall, Christian, McCabe, Kathryn, Michaelovsky, Elena, Ornstein, Claudia, Silversides, Candice, Tran, Oanh, van Duin, Esther DA, Vergaelen, Elfi, Warren, Steve T, Weinberger, Ronnie, Weizman, Abraham, Zhang, Zhengdong, Zwick, Michael, Bearden, Carrie E, Vingerhoets, Claudia, van Amelsvoort, Therese, Eliez, Stephan, Schneider, Maude, Vorstman, Jacob AS, Gothelf, Doron, Zackai, Elaine, Agopian, AJ, Gur, Raquel E, Bassett, Anne S, Emanuel, Beverly S, Goldmuntz, Elizabeth, Mitchell, Laura E, Wang, Tao, and Morrow, Bernice E

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Clinical Research, Human Genome, Heart Disease, Cardiovascular, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Case-Control Studies, Chromosome Deletion, Chromosomes, Human, Pair 22, Cohort Studies, Female, Genome-Wide Association Study, Heart Defects, Congenital, Humans, Linkage Disequilibrium, Male, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Mas, Segmental Duplications, Genomic, International 22q11.2 Brain and Behavior Consortium, CRKL, DiGeorge syndrome, TBX1, chromosome 22q11.2 deletion syndrome, complex trait, congenital heart disease, conotruncal heart defects, copy number variation, genetic association, genetic modifier, haploinsufficiency, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

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.

Published
2020

6. Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome

Author

Óskarsdóttir, Sólveig, Boot, Erik, Crowley, Terrence Blaine, Loo, Joanne C.Y., Arganbright, Jill M., Armando, Marco, Baylis, Adriane L., Breetvelt, Elemi J., Castelein, René M., Chadehumbe, Madeline, Cielo, Christopher M., de Reuver, Steven, Eliez, Stephan, Fiksinski, Ania M., Forbes, Brian J., Gallagher, Emily, Hopkins, Sarah E., Jackson, Oksana A., Levitz-Katz, Lorraine, Klingberg, Gunilla, Lambert, Michele P., Marino, Bruno, Mascarenhas, Maria R., Moldenhauer, Julie, Moss, Edward M., Nowakowska, Beata Anna, Orchanian-Cheff, Ani, Putotto, Carolina, Repetto, Gabriela M., Schindewolf, Erica, Schneider, Maude, Solot, Cynthia B., Sullivan, Kathleen E., Swillen, Ann, Unolt, Marta, Van Batavia, Jason P., Vingerhoets, Claudia, Vorstman, Jacob, Bassett, Anne S., and McDonald-McGinn, Donna M.

Published
2023
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9. Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

Author

Zhao, Yingjie, Guo, Tingwei, Fiksinski, Ania, Breetvelt, Elemi, McDonald‐McGinn, Donna M, Crowley, Terrence B, Diacou, Alexander, Schneider, Maude, Eliez, Stephan, Swillen, Ann, Breckpot, Jeroen, Vermeesch, Joris, Chow, Eva WC, Gothelf, Doron, Duijff, Sasja, Evers, Rens, Amelsvoort, Thérèse A, Bree, Marianne, Owen, Michael, Niarchou, Maria, Bearden, Carrie E, Ornstein, Claudia, Pontillo, Maria, Buzzanca, Antonino, Vicari, Stefano, Armando, Marco, Murphy, Kieran C, Murphy, Clodagh, Garcia‐Minaur, Sixto, Philip, Nicole, Campbell, Linda, Morey‐Cañellas, Jaume, Raventos, Jasna, Rosell, Jordi, Heine‐Suner, Damian, Shprintzen, Robert J, Gur, Raquel E, Zackai, Elaine, Emanuel, Beverly S, Wang, Tao, Kates, Wendy R, Bassett, Anne S, Vorstman, Jacob AS, Morrow, Bernice E, and Consortium, on behalf of the International 22q11 2 Brain and Behavior

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Acquired Cognitive Impairment, Clinical Research, Brain Disorders, Pediatric, Adolescent, Adult, Child, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Female, Humans, Intellectual Disability, Intelligence Tests, Male, 22q11.2 deletion syndrome, deletion size, intellectual disability, IQ, low copy repeat, segmental duplication, International 22q11.2 Brain and Behavior Consortium, Clinical sciences
Abstract

The 22q11.2 deletion syndrome is caused by non-allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A-D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation-SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B-D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort.

Published
2018

11. Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects

Author

Antonarakis, Stylianos E., Biondi, Massimo, Boot, Erik, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Buzzanca, Antonino, Carmel, Miri, Cleynen, Isabelle, Cutler, David, Dallapiccola, Bruno, de la Fuente Sanches, María Angeles, Epstein, Michael P., Evers, Rens, Fernandez, Luis, Fritsch, Rosemarie, Algas, Fernando García, Guo, Tingwei, Gur, Raquel, Hestand, Matthew S., Heung, Tracy, Hooper, Stephen, Jin, Andrea, Kushan-Wells, Leila, Laorden-Nieto, Alejandra Teresa, Lattanzi, Guido, Marshall, Christian, McCabe, Kathryn, Michaelovsky, Elena, Ornstein, Claudia, Silversides, Candice, Tran, Oanh, van Duin, Esther D.A., Vergaelen, Elfi, Warren, Steve T., Weinberger, Ronnie, Weizman, Abraham, Zhang, Zhengdong, Zwick, Michael, Zhao, Yingjie, Diacou, Alexander, Johnston, H. Richard, Musfee, Fadi I., McDonald-McGinn, Donna M., McGinn, Daniel, Crowley, T. Blaine, Repetto, Gabriela M., 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, van den Bree, Marianne, 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, van Amelsvoort, Therese, 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, and Morrow, Bernice E.

Published
2020
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13. Early interventions in risk groups for schizophrenia: what are we waiting for?

Author

Sommer, Iris E, Bearden, Carrie E, van Dellen, Edwin, Breetvelt, Elemi J, Duijff, Sasja N, Maijer, Kim, van Amelsvoort, Therese, de Haan, Lieuwe, Gur, Raquel E, Arango, Celso, Díaz-Caneja, Covadonga M, Vinkers, Christiaan H, and Vorstman, Jacob As

Abstract

Intervention strategies in adolescents at ultra high-risk (UHR) for psychosis are promising for reducing conversion to overt illness, but have only limited impact on functional outcome. Recent studies suggest that cognition does not further decline during the UHR stage. As social and cognitive impairments typically develop before the first psychotic episode and even years before the UHR stage, prevention should also start much earlier in the groups at risk for schizophrenia and other psychiatric disorders. Early intervention strategies could aim to improve stress resilience, optimize brain maturation, and prevent or alleviate adverse environmental circumstances. These strategies should urgently be tested for efficacy: the prevalence of ~1% implies that yearly ~22 in every 100,000 people develop overt symptoms of this illness, despite the fact that for many of them-e.g., children with an affected first-degree family member or carriers of specific genetic variants-increased risk was already identifiable early in life. Our current ability to recognize several risk groups at an early age not only provides an opportunity, but also implies a clinical imperative to act. Time is pressing to investigate preventive interventions in high-risk children to mitigate or prevent the development of schizophrenia and related psychiatric disorders.

Published
2016

14. Cognitive Decline Preceding the Onset of Psychosis in Patients With 22q11.2 Deletion Syndrome

Author

Vorstman, Jacob AS, Breetvelt, Elemi J, Duijff, Sasja N, Eliez, Stephan, Schneider, Maude, Jalbrzikowski, Maria, Armando, Marco, Vicari, Stefano, Shashi, Vandana, Hooper, Stephen R, Chow, Eva WC, Fung, Wai Lun Alan, Butcher, Nancy J, Young, Donald A, McDonald-McGinn, Donna M, Vogels, Annick, van Amelsvoort, Therese, Gothelf, Doron, Weinberger, Ronnie, Weizman, Abraham, Klaassen, Petra WJ, Koops, Sanne, Kates, Wendy R, Antshel, Kevin M, Simon, Tony J, Ousley, Opal Y, Swillen, Ann, Gur, Raquel E, Bearden, Carrie E, Kahn, René S, and Bassett, Anne S

Subjects
Mental Health, Prevention, Brain Disorders, Schizophrenia, Serious Mental Illness, Pediatric, Clinical Research, Mental health, Adolescent, Age Factors, Child, Chromosomes, Human, Pair 22, Cognition Disorders, DiGeorge Syndrome, Female, Humans, Intelligence Tests, Male, Neuropsychological Tests, Prospective Studies, Psychotic Disorders, Risk Factors, Young Adult, International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome, Other Medical and Health Sciences, Psychology, Cognitive Sciences
Abstract

ImportancePatients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk of developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities starting at a young age.ObjectiveTo determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS.Design, setting, and participantsProspective longitudinal cohort study. As part of an international research consortium initiative, we used the largest data set of intelligence (IQ) measurements in patients with 22q11DS reported to date to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 patients with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessments and longitudinal IQ measurements were available for a subset of 411 patients (388 with ≥1 assessment at age 8-24 years).Main outcomes and measuresDiagnosis of a psychotic disorder, initial IQ, longitudinal IQ trajectory, and timing of the last psychiatric assessment with respect to the last IQ test.ResultsAmong 411 patients with 22q11DS, 55 (13.4%) were diagnosed as having a psychotic disorder. The mean (SD) age at the most recent psychiatric assessment was 16.1 (6.2) years. The mean (SD) full-scale IQ at first cognitive assessment was lower in patients who developed a psychotic disorder (65.5 [12.0]) compared with those without a psychotic disorder (74.0 [14.0]). On average, children with 22q11DS showed a mild decline in IQ (full-scale IQ, 7.04 points) with increasing age, particularly in the domain of verbal IQ (9.02 points). In those who developed psychotic illness, this decline was significantly steeper (P

Published
2015

17. W55. REGIONAL BURDEN ANALYSIS OF FUNCTIONAL VARIANTS REVEALS GENOMIC HOTSPOTS ENRICHED FOR REGULATORY ELEMENTS AND OVERLAPPING WITH RECURRENT PATHOGENIC CNVS

Author

Breetvelt, Elemi, primary, Trost, Brett, additional, Engchuan, Worrawat, additional, de Aquino, Marla Mendes, additional, Safarian, Nickie, additional, Thiruvahindrapuram, Bhooma, additional, Lai, Meng-Chuan, additional, Yuen, Ryan, additional, Gallagher, Louise, additional, Szatmari, Peter, additional, Scherer, Steven H., additional, and Vorstman, Jacob, additional

Published
2023
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19. 51. An Emerging Landscape of Genomic Regions Where an Excess of Low Frequency Sequence Variants and Pathogenic CNVs are Associated With ASD and Schizophrenia Risk

Author

Breetvelt, Elemi, primary, Trost, Brett, additional, Engchuan, Worrawat, additional, Mendes de Aquino, Marla, additional, Lai, Meng-Chaun, additional, Thiruvahindrapuram, Bhooma, additional, Zarrei, Mehdi, additional, Yuen, Ryan, additional, Szatmari, Peter, additional, Scherer, Stephen W., additional, and Vorstman, Jacob, additional

Published
2023
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20. Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome

Author

MS Orthopaedie Algemeen, Zorgeenheid Orthopaedie Medisch, Psychosociale zorg patientenzorg, Integrale & Algemene Kindergen Onderzoek, Brain, Óskarsdóttir, Sólveig, Boot, Erik, Crowley, Terrence Blaine, Loo, Joanne C.Y., Arganbright, Jill M., Armando, Marco, Baylis, Adriane L., Breetvelt, Elemi J., Castelein, René M., Chadehumbe, Madeline, Cielo, Christopher M., de Reuver, Steven, Eliez, Stephan, Fiksinski, Ania M., Forbes, Brian J., Gallagher, Emily, Hopkins, Sarah E., Jackson, Oksana A., Levitz-Katz, Lorraine, Klingberg, Gunilla, Lambert, Michele P., Marino, Bruno, Mascarenhas, Maria R., Moldenhauer, Julie, Moss, Edward M., Nowakowska, Beata Anna, Orchanian-Cheff, Ani, Putotto, Carolina, Repetto, Gabriela M., Schindewolf, Erica, Schneider, Maude, Solot, Cynthia B., Sullivan, Kathleen E., Swillen, Ann, Unolt, Marta, Van Batavia, Jason P., Vingerhoets, Claudia, Vorstman, Jacob, Bassett, Anne S., McDonald-McGinn, Donna M., MS Orthopaedie Algemeen, Zorgeenheid Orthopaedie Medisch, Psychosociale zorg patientenzorg, Integrale & Algemene Kindergen Onderzoek, Brain, Óskarsdóttir, Sólveig, Boot, Erik, Crowley, Terrence Blaine, Loo, Joanne C.Y., Arganbright, Jill M., Armando, Marco, Baylis, Adriane L., Breetvelt, Elemi J., Castelein, René M., Chadehumbe, Madeline, Cielo, Christopher M., de Reuver, Steven, Eliez, Stephan, Fiksinski, Ania M., Forbes, Brian J., Gallagher, Emily, Hopkins, Sarah E., Jackson, Oksana A., Levitz-Katz, Lorraine, Klingberg, Gunilla, Lambert, Michele P., Marino, Bruno, Mascarenhas, Maria R., Moldenhauer, Julie, Moss, Edward M., Nowakowska, Beata Anna, Orchanian-Cheff, Ani, Putotto, Carolina, Repetto, Gabriela M., Schindewolf, Erica, Schneider, Maude, Solot, Cynthia B., Sullivan, Kathleen E., Swillen, Ann, Unolt, Marta, Van Batavia, Jason P., Vingerhoets, Claudia, Vorstman, Jacob, Bassett, Anne S., and McDonald-McGinn, Donna M.

Published
2023

24. A Regional Burden of Sequence-Level Variation in the 22q11.2 Region Influences Schizophrenia Risk and Educational Attainment

Author

Medisch Oncologische Disciplines, Team Smart 1, Epi Kanker Team B, Cancer, Verpleegafdeling Cardiologie, Onderzoek Precision medicine, Circulatory Health, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Onderzoeksgroep 2, Brain, Onderzoeksgroep 11, Onderzoek, Breetvelt, Elemi J., Smit, Karel C., van Setten, Jessica, Merico, Daniele, Wang, Xiao, Vaartjes, Ilonca, Bassett, Anne S., Boks, Marco P.M., Szatmari, Peter, Scherer, Stephen W., Kahn, René S., Vorstman, Jacob A.S., Medisch Oncologische Disciplines, Team Smart 1, Epi Kanker Team B, Cancer, Verpleegafdeling Cardiologie, Onderzoek Precision medicine, Circulatory Health, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Onderzoeksgroep 2, Brain, Onderzoeksgroep 11, Onderzoek, Breetvelt, Elemi J., Smit, Karel C., van Setten, Jessica, Merico, Daniele, Wang, Xiao, Vaartjes, Ilonca, Bassett, Anne S., Boks, Marco P.M., Szatmari, Peter, Scherer, Stephen W., Kahn, René S., and Vorstman, Jacob A.S.

Published
2022

25. A normative chart for cognitive development in a genetically selected population

Author

Integrale & Algemene Kindergeneeskunde, Onderzoeksgroep 11, Brain, Ontwikkelingsstoornissen Med., AIOS Psychiatrie, Onderzoek, Integrale & Alg. Kindergen Patientenzorg, Cluster D, Child Health, Fiksinski, Ania M, Bearden, Carrie E, Bassett, Anne S, Kahn, Rene S, Zinkstok, Janneke R, Hooper, Stephen R, Tempelaar, Wanda, Vorstman, Jacob A S, Breetvelt, Elemi J, 22q11DS International Consortium on Brain and Behavior, Integrale & Algemene Kindergeneeskunde, Onderzoeksgroep 11, Brain, Ontwikkelingsstoornissen Med., AIOS Psychiatrie, Onderzoek, Integrale & Alg. Kindergen Patientenzorg, Cluster D, Child Health, Fiksinski, Ania M, Bearden, Carrie E, Bassett, Anne S, Kahn, Rene S, Zinkstok, Janneke R, Hooper, Stephen R, Tempelaar, Wanda, Vorstman, Jacob A S, Breetvelt, Elemi J, and 22q11DS International Consortium on Brain and Behavior

Published
2022

26. Within-family influences on dimensional neurobehavioral traits in a high-risk genetic model

Author

Onderzoek, Ontwikkelingsstoornissen Med., Onderzoeksgroep 11, Brain, Fiksinski, Ania M, Heung, Tracy, Corral, Maria, Breetvelt, Elemi J, Costain, Gregory, Marshall, Christian R, Kahn, Rene S, Vorstman, Jacob A S, Bassett, Anne S, Onderzoek, Ontwikkelingsstoornissen Med., Onderzoeksgroep 11, Brain, Fiksinski, Ania M, Heung, Tracy, Corral, Maria, Breetvelt, Elemi J, Costain, Gregory, Marshall, Christian R, Kahn, Rene S, Vorstman, Jacob A S, and Bassett, Anne S

Published
2022

27. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption

Author

Schumann, Gunter, Coin, Lachlan J., Lourdusamy, Anbarasu, Charoen, Pimphen, Berger, Karen H., Stacey, David, Desrivières, Sylvane, Aliev, Fazil A., Khan, Anokhi A., Amin, Najaf, Aulchenko, Yurii S., Bakalkin, Georgy, Bakker, Stephan J., Balkau, Beverley, Beulens, Joline W., Bilbao, Ainhoa, de Boer, Rudolf A., Beury, Delphine, Bots, Michiel L., Breetvelt, Elemi J., Cauchi, Stéphane, Cavalcanti-Proença, Christine, Chambers, John C., Clarke, Toni-Kim, Dahmen, Norbert, de Geus, Eco J., Dick, Danielle, Ducci, Francesca, Easton, Alanna, Edenberg, Howard J., Esk, Tõnu, Fernández-Medarde, Alberto, Foroud, Tatiana, Freimer, Nelson B., Girault, Jean-Antoine, Grobbee, Diederick E., Guarrera, Simonetta, Gudbjartsson, Daniel F., Hartikainen, Anna-Liisa, Heath, Andrew C., Hesselbrock, Victor, Hofman, Albert, Hottenga, Jouke-Jan, Isohanni, Matti K., Kaprio, Jaakko, Khaw, Kay-Tee, Kuehnel, Brigitte, Laitinen, Jaana, Lobbens, Stéphane, Luan, Jian'an, Mangino, Massimo, Maroteaux, Matthieu, Matullo, Giuseppe, McCarthy, Mark I., Mueller, Christian, Navis, Gerjan, Numans, Mattijs E., Núñez, Alejandro, Nyholt, Dale R., Onland-Moret, Charlotte N., Oostra, Ben A., O'Reilly, Paul F., Palkovits, Miklos, Penninx, Brenda W., Polidoro, Silvia, Pouta, Anneli, Prokopenko, Inga, Ricceri, Fulvio, Santos, Eugenio, Smit, Johannes H., Soranzo, Nicole, Song, Kijoung, Sovio, Ulla, Stumvoll, Michael, Surakk, Ida, Thorgeirsson, Thorgeir E., Thorsteinsdottir, Unnur, Troakes, Claire, Tyrfingsson, Thorarinn, Tönjes, Anke, Uiterwaal, Cuno S., Uitterlinden, Andre G., van der Harst, Pim, van der Schouw, Yvonne T., Staehlin, Oliver, Vogelzangs, Nicole, Vollenweider, Peter, Waeber, Gerard, Wareham, Nicholas J., Waterworth, Dawn M., Whitfield, John B., Wichmann, Erich H., Willemsen, Gonneke, Witteman, Jacqueline C., Yuan, Xin, Zhai, Guangju, Zhao, Jing H., Zhang, Weihua, Martin, Nicholas G., Metspalu, Andres, Doering, Angela, Scott, James, Spector, Tim D., Loos, Ruth J., Boomsma, Dorret I., Mooser, Vincent, Peltonen, Leena, Stefansson, Kari, van Duijn, Cornelia M., Vineis, Paolo, Sommer, Wolfgang H., Kooner, Jaspal S., Spanagel, Rainer, Heberlein, Ulrike A., Jarvelin, Marjo-Riitta, Elliott, Paul, and Singer, Burton H.

Published
2011

29. Within-family influences on dimensional neurobehavioral traits in a high-risk genetic model.

Author

Fiksinski, Ania M., Heung, Tracy, Corral, Maria, Breetvelt, Elemi J., Costain, Gregory, Marshall, Christian R., Kahn, Rene S., Vorstman, Jacob A.S., and Bassett, Anne S.

Subjects
SCHIZOPHRENIA risk factors, GENETICS of schizophrenia, SOCIAL participation, BIOLOGICAL models, PSYCHOLOGY of parents, 22Q11 deletion syndrome, EFFECT sizes (Statistics), QUANTITATIVE research, COGNITION, REGRESSION analysis, GENETIC variation, RISK assessment, COMPARATIVE studies, INTRACLASS correlation, DESCRIPTIVE statistics, DISEASE susceptibility, COGNITIVE testing, SOCIAL skills, PHENOTYPES, MOTOR ability, INTELLIGENCE tests, DISEASE complications
Abstract

Background: Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders. Methods: We quantitatively assessed cognitive (FSIQ, VIQ, PIQ), social, and motor functioning in 82 adult individuals with a de novo 22q11.2 deletion (22 with schizophrenia), and 148 of their unaffected parents. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures. Results: Proband-parent intra-class correlations (ICC) were significant for cognitive measures (e.g. FSIQ ICC = 0.549, p < 0.0001), but not for social or motor measures. Compared to biparental scores, the 22q11.2 deletion conferred significant impairments for all phenotypes assessed (effect sizes −1.39 to −2.07 s.d.), strongest for PIQ. There were further decrements in those with schizophrenia. Regression models explained up to 37.7% of the variance in IQ and indicated that for proband IQ, parental IQ had larger effects than schizophrenia. Conclusions: This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups. [ABSTRACT FROM AUTHOR]

Published
2022
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30. A normative chart for cognitive development in a genetically selected population

Author

Fiksinski, Ania M., Bearden, Carrie E., Bassett, Anne S., Kahn, René S., Zinkstok, Janneke R., Hooper, Stephen R., Tempelaar, Wanda, McDonald-McGinn, Donna, Swillen, Ann, Emanuel, Beverly, Morrow, Bernice, Gur, Raquel, Chow, Eva, van den Bree, Marianne, Vermeesch, Joris, Warren, Stephen, Owen, Michael, van Amelsvoort, Therese, Eliez, Stephan, Gothelf, Doron, Arango, Celso, Kates, Wendy, Simon, Tony, Murphy, Kieran, Repetto, Gabriela, Suner, Damian Heine, Vicari, Stefano, Cubells, Joseph, Armando, Marco, Philip, Nicole, Campbell, Linda, Garcia-Minaur, Sixto, Schneider, Maude, Shashi, Vandana, Vorstman, Jacob, Breetvelt, Elemi J., RS: MHeNs - R2 - Mental Health, and Psychiatrie & Neuropsychologie

Subjects
Adult, DISORDERS, Population, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], CHILDHOOD, CHILDREN, ADULTHOOD, Article, 03 medical and health sciences, 0302 clinical medicine, PSYCHOSIS, Cognition, Chart, medicine, Cognitive development, DiGeorge Syndrome, Humans, 22Q11.2 DELETION SYNDROME, BRAIN, education, Association (psychology), Pharmacology, Intelligence Tests, education.field_of_study, DECLINE, medicine.disease, RETT-SYNDROME, 030227 psychiatry, Psychiatry and Mental health, Schizophrenia, Sample size determination, Normative, Psychology, 030217 neurology & neurosurgery, BEHAVIOR, Clinical psychology
Abstract

Item does not contain fulltext Certain pathogenic genetic variants impact neurodevelopment and cause deviations from typical cognitive trajectories. Understanding variant-specific cognitive trajectories is clinically important for informed monitoring and identifying patients at risk for comorbid conditions. Here, we demonstrate a variant-specific normative chart for cognitive development for individuals with 22q11.2 deletion syndrome (22q11DS). We used IQ data from 1365 individuals with 22q11DS to construct variant-specific normative charts for cognitive development (Full Scale, Verbal, and Performance IQ). This allowed us to calculate Z-scores for each IQ datapoint. Then, we calculated the change between first and last available IQ assessments (delta Z-IQ-scores) for each individual with longitudinal IQ data (n = 708). We subsequently investigated whether using the variant-specific IQ-Z-scores would decrease required sample size to detect an effect with schizophrenia risk, as compared to standard IQ-scores. The mean Z-IQ-scores for FSIQ, VIQ, and PIQ were close to 0, indicating that participants had IQ-scores as predicted by the normative chart. The mean delta-Z-IQ-scores were equally close to 0, demonstrating a good fit of the normative chart and indicating that, as a group, individuals with 22q11DS show a decline in IQ-scores as they grow into adulthood. Using variant-specific IQ-Z-scores resulted in 30% decrease of required sample size, as compared to the standard IQ-based approach, to detect the association between IQ-decline and schizophrenia (p

Published
2021

31. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome

Author

Onderzoek, Beeldverwerking ISI, Chair, Directie Raad van Bestuur, Psychosociale zorg patientenzorg, Brain, Child Health, Onderzoeksgroep 11, 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., van den Bree, Marianne, Emanuel, Beverly S., Vermeesch, Joris R., van Amelsvoort, Therese, 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 M., Shashi, Vandana, Simon, Tony J., Suñer, Damiàn Heine, Vicari, Stefano, Scherer, Stephen W., Epstein, Michael P., Warren, Stephen T., Morrison, Sinead, Chawner, Samuel, Vingerhoets, Claudia, Breckpot, Jeroen, Vergaelen, Elfi, Vogels, Annick, Monks, Stephen, Prasad, Sarah E., Schneider, Maude, Duijff, Sasja N., Kahn, René S., Houben, Michiel, Vorstman, Jacob A.S., International 22q11.2 Brain and Behavior Consortium, Onderzoek, Beeldverwerking ISI, Chair, Directie Raad van Bestuur, Psychosociale zorg patientenzorg, Brain, Child Health, Onderzoeksgroep 11, 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., van den Bree, Marianne, Emanuel, Beverly S., Vermeesch, Joris R., van Amelsvoort, Therese, 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 M., Shashi, Vandana, Simon, Tony J., Suñer, Damiàn Heine, Vicari, Stefano, Scherer, Stephen W., Epstein, Michael P., Warren, Stephen T., Morrison, Sinead, Chawner, Samuel, Vingerhoets, Claudia, Breckpot, Jeroen, Vergaelen, Elfi, Vogels, Annick, Monks, Stephen, Prasad, Sarah E., Schneider, Maude, Duijff, Sasja N., Kahn, René S., Houben, Michiel, Vorstman, Jacob A.S., and International 22q11.2 Brain and Behavior Consortium

Published
2020

34. RETRACTED: Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Author

Antshel, Kevin, Arango, Celso, Armando, Marco, Bassett, Anne, Bearden, Carrie, Boot, Erik, Bravo-Sanchez, Marta, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Campbell, Linda, Carmel, Miri, Chow, Eva, Crowley, T. Blaine, Cubells, Joseph, Cutler, David, Demaerel, Wolfram, Digilio, Maria Cristina, Duijff, Sasja, Eliez, Stephan, Emanuel, Beverly, Epstein, Michael, Evers, Rens, Fernandez Garcia-Moya, Luis, Fiksinski, Ania, Fraguas, David, Fremont, Wanda, Fritsch, Rosemarie, Garcia-Minaur, Sixto, Golden, Aaron, Gothelf, Doron, Guo, Tingwei, Gur, Ruben, Gur, Raquel, Heine-Suner, Damian, Hestand, Matthew, Hooper, Stephen, Kates, Wendy, Kushan, Leila, Laorden-Nieto, Alejandra, Maeder, Johanna, Marino, Bruno, Marshall, Christian, McCabe, Kathryn, McDonald-McGinn, Donna, Michaelovosky, Elena, Morrow, Bernice, Moss, Edward, Mulle, Jennifer, Murphy, Declan, Murphy, Kieran, Murphy, Clodagh, Niarchou, Maria, Ornstein, Claudia, Owen, Michael, Philip, Nicole, Repetto, Gabriela, Schneider, Maude, Shashi, Vandana, Simon, Tony, Swillen, Ann, Tassone, Flora, Unolt, Marta, van Amelsvoort, Therese, van den Bree, Marianne, Van Duin, Esther, Vergaelen, Elfi, Vermeesch, Joris, Vicari, Stefano, Vingerhoets, Claudia, Vorstman, Jacob, Warren, Steve, Weinberger, Ronnie, Weisman, Omri, Weizman, Abraham, Zackai, Elaine, Zhang, Zhengdong, Zwick, Michael, Hestand, Matthew S., López-Sánchez, Marcos, Pérez-Jurado, Luis A., McDonald-McGinn, Donna M., Emanuel, Beverly S., Morrow, Bernice E., Breckpot, Jeroen, Devriendt, Koenraad, and Vermeesch, Joris R.

Published
2017
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35. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Author

Marees, Andries T, Hammerschlag, Anke R, Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J, Denys, Damiaan, Gamazon, Eric R, Li-Gao, Ruifang, Breetvelt, Elemi J, de Groot, Mark C H, Galesloot, Tessel E, Vermeulen, Sita H, Poppelaars, Jan L, Souverein, Patrick C, Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R, Stringa, Najada, Mook-Kanamori, Dennis O, Vaartjes, Ilonca, Kiemeney, Lambertus A, den Heijer, Martin, van Schoor, Natasja M, Klungel, Olaf H, Maitland-Van der Zee, Anke H, Schmidt, Marjanka K, Polderman, Tinca J C, van der Leij, Andries R, Posthuma, Danielle, Derks, Eske M, Marees, Andries T, Hammerschlag, Anke R, Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J, Denys, Damiaan, Gamazon, Eric R, Li-Gao, Ruifang, Breetvelt, Elemi J, de Groot, Mark C H, Galesloot, Tessel E, Vermeulen, Sita H, Poppelaars, Jan L, Souverein, Patrick C, Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R, Stringa, Najada, Mook-Kanamori, Dennis O, Vaartjes, Ilonca, Kiemeney, Lambertus A, den Heijer, Martin, van Schoor, Natasja M, Klungel, Olaf H, Maitland-Van der Zee, Anke H, Schmidt, Marjanka K, Polderman, Tinca J C, van der Leij, Andries R, Posthuma, Danielle, and Derks, Eske M

Abstract

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use.METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses.RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use.DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Published
2018

36. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Author

Marees, Andries T., Hammerschlag, Anke R., Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J., Denys, Damiaan, Gamazon, Eric R., Li-Gao, Ruifang, Breetvelt, Elemi J., de Groot, Mark C.H., Galesloot, Tessel E., Vermeulen, Sita H., Poppelaars, Jan L., Souverein, Patrick C., Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R., Stringa, Najada, Mook-Kanamori, Dennis O., Vaartjes, Ilonca, Kiemeney, Lambertus A., den Heijer, Martin, van Schoor, Natasja M., Klungel, Olaf H., Maitland-Van der Zee, Anke H., Schmidt, Marjanka K., Polderman, Tinca J.C., van der Leij, Andries R., Posthuma, Danielle, Derks, Eske M., Marees, Andries T., Hammerschlag, Anke R., Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J., Denys, Damiaan, Gamazon, Eric R., Li-Gao, Ruifang, Breetvelt, Elemi J., de Groot, Mark C.H., Galesloot, Tessel E., Vermeulen, Sita H., Poppelaars, Jan L., Souverein, Patrick C., Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R., Stringa, Najada, Mook-Kanamori, Dennis O., Vaartjes, Ilonca, Kiemeney, Lambertus A., den Heijer, Martin, van Schoor, Natasja M., Klungel, Olaf H., Maitland-Van der Zee, Anke H., Schmidt, Marjanka K., Polderman, Tinca J.C., van der Leij, Andries R., Posthuma, Danielle, and Derks, Eske M.

Published
2018

37. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Marees, Andries T, Hammerschlag, Anke R, Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J, Denys, Damiaan, Gamazon, Eric R, Li-Gao, Ruifang, Breetvelt, Elemi J, de Groot, Mark C H, Galesloot, Tessel E, Vermeulen, Sita H, Poppelaars, Jan L, Souverein, Patrick C, Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R, Stringa, Najada, Mook-Kanamori, Dennis O, Vaartjes, Ilonca, Kiemeney, Lambertus A, den Heijer, Martin, van Schoor, Natasja M, Klungel, Olaf H, Maitland-Van der Zee, Anke H, Schmidt, Marjanka K, Polderman, Tinca J C, van der Leij, Andries R, Posthuma, Danielle, Derks, Eske M, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Marees, Andries T, Hammerschlag, Anke R, Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J, Denys, Damiaan, Gamazon, Eric R, Li-Gao, Ruifang, Breetvelt, Elemi J, de Groot, Mark C H, Galesloot, Tessel E, Vermeulen, Sita H, Poppelaars, Jan L, Souverein, Patrick C, Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R, Stringa, Najada, Mook-Kanamori, Dennis O, Vaartjes, Ilonca, Kiemeney, Lambertus A, den Heijer, Martin, van Schoor, Natasja M, Klungel, Olaf H, Maitland-Van der Zee, Anke H, Schmidt, Marjanka K, Polderman, Tinca J C, van der Leij, Andries R, Posthuma, Danielle, and Derks, Eske M

Published
2018

38. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Author

Ontwikkelingsstoornissen Med., LKCH Research Hoofdanalist, CDL Arcadia, Other research (not in main researchprogram), Cardiovasculaire Epi Team 4, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Global Health, JC onderzoeksprogramma Methodologie, Marees, Andries T., Hammerschlag, Anke R., Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J., Denys, Damiaan, Gamazon, Eric R., Li-Gao, Ruifang, Breetvelt, Elemi J., de Groot, Mark C.H., Galesloot, Tessel E., Vermeulen, Sita H., Poppelaars, Jan L., Souverein, Patrick C., Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R., Stringa, Najada, Mook-Kanamori, Dennis O., Vaartjes, Ilonca, Kiemeney, Lambertus A., den Heijer, Martin, van Schoor, Natasja M., Klungel, Olaf H., Maitland-Van der Zee, Anke H., Schmidt, Marjanka K., Polderman, Tinca J.C., van der Leij, Andries R., Posthuma, Danielle, Derks, Eske M., Ontwikkelingsstoornissen Med., LKCH Research Hoofdanalist, CDL Arcadia, Other research (not in main researchprogram), Cardiovasculaire Epi Team 4, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Global Health, JC onderzoeksprogramma Methodologie, Marees, Andries T., Hammerschlag, Anke R., Bastarache, Lisa, de Kluiver, Hilde, Vorspan, Florence, van den Brink, Wim, Smit, Dirk J., Denys, Damiaan, Gamazon, Eric R., Li-Gao, Ruifang, Breetvelt, Elemi J., de Groot, Mark C.H., Galesloot, Tessel E., Vermeulen, Sita H., Poppelaars, Jan L., Souverein, Patrick C., Keeman, Renske, de Mutsert, Renée, Noordam, Raymond, Rosendaal, Frits R., Stringa, Najada, Mook-Kanamori, Dennis O., Vaartjes, Ilonca, Kiemeney, Lambertus A., den Heijer, Martin, van Schoor, Natasja M., Klungel, Olaf H., Maitland-Van der Zee, Anke H., Schmidt, Marjanka K., Polderman, Tinca J.C., van der Leij, Andries R., Posthuma, Danielle, and Derks, Eske M.

Published
2018

39. Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Author

Demaerel, Wolfram, Hestand, Matthew S., Vergaelen, Elfi, Swillen, Ann, López-Sánchez, Marcos, Pérez-Jurado, Luis A., Mcdonald-Mcginn, Donna, Zackai, Elaine, Emanuel, Beverly, Morrow, Bernice E., Breckpot, Jeroen, Devriendt, Koenraad, Vermeesch, Joris, Antshel, Kevin, Arango, Celso, Armando, Marco, Bassett, Anne, Bearden, Carrie, Boot, Erik, Bravo-sanchez, Marta, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy, Campbell, Linda, Carmel, Miri, Chow, Eva, Crowley, T. Blaine, Cubells, Joseph, Cutler, David, Digilio, Maria Cristina, Duijff, Sasja, Eliez, Stephan, Epstein, Michael, Evers, Rens, Fernandez Garcia-moya, Luis, Fiksinski, Ania, Fraguas, David, Fremont, Wanda, Fritsch, Rosemarie, Garcia-Minaur, Sixto, Golden, Aaron, Gothelf, Doron, Guo, Tingwei, Gur, Ruben, Murphy, Declan, Murphy, Kieran, Murphy, Clodagh, and Van Amelsvoort, Therese

Subjects
Genomic disorder, 22q11.2 deletion syndrome, low-copy repeats, Genetics, VCFS, Genetics(clinical), 22q11.2DS, microdeletion, inversion polymorphism, segmental duplications, DiGeorge syndrome, fiber-FISH
Abstract

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders.

Published
2017
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41. Retraction Notice to: Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Author

Demaerel, Wolfram, primary, Hestand, Matthew S., additional, Vergaelen, Elfi, additional, Swillen, Ann, additional, López-Sánchez, Marcos, additional, Pérez-Jurado, Luis A., additional, McDonald-McGinn, Donna M., additional, Zackai, Elaine, additional, Emanuel, Beverly S., additional, Morrow, Bernice E., additional, Breckpot, Jeroen, additional, Devriendt, Koenraad, additional, Vermeesch, Joris R., additional, Antshel, Kevin, additional, Arango, Celso, additional, Armando, Marco, additional, Bassett, Anne, additional, Bearden, Carrie, additional, Boot, Erik, additional, Bravo-Sanchez, Marta, additional, Breetvelt, Elemi, additional, Busa, Tiffany, additional, Butcher, Nancy, additional, Campbell, Linda, additional, Carmel, Miri, additional, Chow, Eva, additional, Crowley, T. Blaine, additional, Cubells, Joseph, additional, Cutler, David, additional, Demaerel, Wolfram, additional, Digilio, Maria Cristina, additional, Duijff, Sasja, additional, Eliez, Stephan, additional, Emanuel, Beverly, additional, Epstein, Michael, additional, Evers, Rens, additional, Fernandez Garcia-Moya, Luis, additional, Fiksinski, Ania, additional, Fraguas, David, additional, Fremont, Wanda, additional, Fritsch, Rosemarie, additional, Garcia-Minaur, Sixto, additional, Golden, Aaron, additional, Gothelf, Doron, additional, Guo, Tingwei, additional, Gur, Ruben, additional, Gur, Raquel, additional, Heine-Suner, Damian, additional, Hestand, Matthew, additional, Hooper, Stephen, additional, Kates, Wendy, additional, Kushan, Leila, additional, Laorden-Nieto, Alejandra, additional, Maeder, Johanna, additional, Marino, Bruno, additional, Marshall, Christian, additional, McCabe, Kathryn, additional, McDonald-McGinn, Donna, additional, Michaelovosky, Elena, additional, Morrow, Bernice, additional, Moss, Edward, additional, Mulle, Jennifer, additional, Murphy, Declan, additional, Murphy, Kieran, additional, Murphy, Clodagh, additional, Niarchou, Maria, additional, Ornstein, Claudia, additional, Owen, Michael, additional, Philip, Nicole, additional, Repetto, Gabriela, additional, Schneider, Maude, additional, Shashi, Vandana, additional, Simon, Tony, additional, Tassone, Flora, additional, Unolt, Marta, additional, van Amelsvoort, Therese, additional, van den Bree, Marianne, additional, Van Duin, Esther, additional, Vermeesch, Joris, additional, Vicari, Stefano, additional, Vingerhoets, Claudia, additional, Vorstman, Jacob, additional, Warren, Steve, additional, Weinberger, Ronnie, additional, Weisman, Omri, additional, Weizman, Abraham, additional, Zhang, Zhengdong, additional, and Zwick, Michael, additional

Published
2018
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42. Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use

Author

Marees, Andries T., primary, Hammerschlag, Anke R., additional, Bastarache, Lisa, additional, de Kluiver, Hilde, additional, Vorspan, Florence, additional, van den Brink, Wim, additional, Smit, Dirk J., additional, Denys, Damiaan, additional, Gamazon, Eric R., additional, Li-Gao, Ruifang, additional, Breetvelt, Elemi J., additional, de Groot, Mark C.H., additional, Galesloot, Tessel E., additional, Vermeulen, Sita H., additional, Poppelaars, Jan L., additional, Souverein, Patrick C., additional, Keeman, Renske, additional, de Mutsert, Renée, additional, Noordam, Raymond, additional, Rosendaal, Frits R., additional, Stringa, Najada, additional, Mook-Kanamori, Dennis O., additional, Vaartjes, Ilonca, additional, Kiemeney, Lambertus A., additional, den Heijer, Martin, additional, van Schoor, Natasja M., additional, Klungel, Olaf H., additional, Maitland-Van der Zee, Anke H., additional, Schmidt, Marjanka K., additional, Polderman, Tinca J.C., additional, van der Leij, Andries R., additional, Posthuma, Danielle, additional, and Derks, Eske M., additional

Published
2018
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48. Nested Inversion Polymorphisms Predispose Chromosome 22q11.2 to Meiotic Rearrangements

Author

Ontwikkelingsstoornissen Med., Psychosociale zorg patientenzorg, Brain, Child Health, Onderzoek, Demaerel, Wolfram, Hestand, Matthew S., Vergaelen, Elfi, Swillen, Ann, López-Sánchez, Marcos, Pérez-Jurado, Luis A., McDonald-Mcginn, Donna M., Zackai, Elaine, Emanuel, Beverly S., Morrow, Bernice E., Breckpot, Jeroen, Devriendt, Koenraad, Vermeesch, Joris R., Antshel, Kevin M., Arango, Celso, Armando, Marco, Bassett, Anne S., Bearden, Carrie E., Boot, Erik, Bravo-Sanchez, Marta, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy J., Campbell, Linda E., Carmel, Miri, Chow, Eva W C, Crowley, T. Blaine, Cubells, Joseph, Cutler, David, Digilio, Maria Cristina, Duijff, Sasja, Eliez, Stephan, Epstein, Michael P., Evers, Rens, Fernandez Garcia-Moya, Luis, Fiksinski, Ania, Fraguas, David, Fremont, Wanda, Fritsch, Rosemarie, Garcia-Minaur, Sixto, Golden, Aaron, Gothelf, Doron, Guo, Tingwei, Gur, Ruben C., Gur, Raquel E., Heine-Suner, Damian, Hestand, Matthew, Vorstman, Jacob, International 22q11.2 Brain and Behavior Consortium, Ontwikkelingsstoornissen Med., Psychosociale zorg patientenzorg, Brain, Child Health, Onderzoek, Demaerel, Wolfram, Hestand, Matthew S., Vergaelen, Elfi, Swillen, Ann, López-Sánchez, Marcos, Pérez-Jurado, Luis A., McDonald-Mcginn, Donna M., Zackai, Elaine, Emanuel, Beverly S., Morrow, Bernice E., Breckpot, Jeroen, Devriendt, Koenraad, Vermeesch, Joris R., Antshel, Kevin M., Arango, Celso, Armando, Marco, Bassett, Anne S., Bearden, Carrie E., Boot, Erik, Bravo-Sanchez, Marta, Breetvelt, Elemi, Busa, Tiffany, Butcher, Nancy J., Campbell, Linda E., Carmel, Miri, Chow, Eva W C, Crowley, T. Blaine, Cubells, Joseph, Cutler, David, Digilio, Maria Cristina, Duijff, Sasja, Eliez, Stephan, Epstein, Michael P., Evers, Rens, Fernandez Garcia-Moya, Luis, Fiksinski, Ania, Fraguas, David, Fremont, Wanda, Fritsch, Rosemarie, Garcia-Minaur, Sixto, Golden, Aaron, Gothelf, Doron, Guo, Tingwei, Gur, Ruben C., Gur, Raquel E., Heine-Suner, Damian, Hestand, Matthew, Vorstman, Jacob, and International 22q11.2 Brain and Behavior Consortium

Published
2017

49. Explaining the variable penetrance of CNVs : Parental intelligence modulates expression of intellectual impairment caused by the 22q11.2 deletion

Author

Klaassen, Petra, Duijff, Sasja, Swanenburg de Veye, Henriëtte, Beemer, Frits, Sinnema, Gerben, Breetvelt, Elemi, Schappin, Renske, and Vorstman, Jacob

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Copy number variants, 22q11.2 deletion syndrome, mental disorders, Intelligence, Journal Article, Genetics(clinical)
Abstract

The role of rare genetic variants, in particular copy number variants (CNVs), in the etiology of neurodevelopmental disorders is becoming increasingly clear. While the list of these disorder-related CNVs continues to lengthen, it has also become clear that in nearly all genetic variants the proportion of carriers who express the associated phenotype is far from 100%. To understand this variable penetrance of CNVs it is important to realize that even the largest CNVs represent only a tiny fraction of the entire genome. Therefore, part of the mechanism underlying the variable penetrance of CNVs is likely the modulatory impact of the rest of the genome. In the present study we used the 22q11DS as a model to examine whether the observed penetrance of intellectual impairment-one of the main phenotypes associated with 22q11DS-is modulated by the intellectual level of their parents, for which we used the parents' highest level of education as a proxy. Our results, based on data observed in 171 children with 22q11DS in the age range of 5-15 years, showed a significant association between estimated parental cognitive level and intelligence in offspring (full scale, verbal and performance IQ), with the largest effect size for verbal IQ. These results suggest that possible mechanisms involved in the variable penetrance observed in CNVs include the impact of genetic background and/or environmental influences.

Published
2016

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