TY - JOUR
T1 - Reciprocal duplication of the williams-beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia
AU - Mulle, Jennifer Gladys
AU - Pulver, Ann E.
AU - McGrath, John A.
AU - Wolyniec, Paula S.
AU - Dodd, Anne F.
AU - Cutler, David J.
AU - Sebat, Jonathan
AU - Malhotra, Dheeraj
AU - Nestadt, Gerald
AU - Conrad, Donald F.
AU - Hurles, Matthew
AU - Barnes, Chris P.
AU - Ikeda, Masashi
AU - Iwata, Nakao
AU - Levinson, Douglas F.
AU - Gejman, Pablo V.
AU - Sanders, Alan R.
AU - Duan, Jubao
AU - Mitchell, Adele A.
AU - Peter, Inga
AU - Sklar, Pamela
AU - O'Dushlaine, Colm T.
AU - Grozeva, Detelina
AU - O'Donovan, Michael C.
AU - Owen, Michael J.
AU - Hultman, Christina M.
AU - Kähler, Anna K.
AU - Sullivan, Patrick F.
AU - Kirov, George
AU - Warren, Stephen T.
N1 - Funding Information:
Dr. Mulle reports a consultancy with the Centers for Disease Control. Professors Owen, O’Donovan, and Kirov have received research funding from the Wellcome Trust and the Medical Research Council, London, United Kingdom. The Bulgarian Trios were recruited with a Grant from the Janssen Research Foundation, Beerse, Belgium. Dr. Sullivan was a member of the Scientific Advisory Board of Expression Analysis (Durham, North Carolina). Co-authors Pulver, McGrath, Wolyniec, Dodd, Cutler, Sebat, Malhotra, Nestadt, Conrad, Hurles, Barnes, Ikeda, Iwata, Levinson, Gejman, Sanders, Duan, Mitchell, Peter, Sklar, O’Dushlaine, Grozeva, Hultman, Kähler, and Warren reported no biomedical financial interests or potential conflicts of interest.
Funding Information:
Funding for this study was provided by National Institutes of Health Grants MH080129 and MH083722 to STW and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award to JGM. Support was provided by MH077139 (PFS), the Stanley Center for Psychiatric Research at the Broad Institute from a Grant from Stanley Medical Research Institute, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, ALF grant from Swedish County Council, and Söderström Königska Foundation. Funding support for the companion studies, Genome-Wide Association Study of Schizophrenia (Genetic Association Information Network [GAIN]) and Molecular Genetics of Schizophrenia–nonGAIN Sample (MGS_nonGAIN), was provided by Genomics Research Branch at the National Institute of Mental Health and the genotyping and analysis of samples was provided through GAIN and under the Molecular Genetics of Schizophrenia (MGS) U01s: MH79469 and MH79470. Assistance with data cleaning was provided by the National Center for Biotechnology Information. The MGS datasets used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession numbers phs000021.v2.p1 (GAIN) and phs000167.v1.p1 (nonGAIN). Samples and associated phenotype data for the MGS genome-wide association study were collected under the following grants: National Institute of Mental Health Schizophrenia Genetics Initiative U01s: MH46276 (C.R. Cloninger), MH46289 (C. Kaufmann), and MH46318 (M.T. Tsuang); and MGS Part 1 and MGS Part 2 R01s: MH67257 (N.G. Buccola), MH59588 (B.J. Mowry), MH59571 (P.V. Gejman), MH59565 (R. Freedman), MH59587 (F. Amin), MH60870 (W.F. Byerley), MH59566 (D.W. Black), MH59586 (J.M. Silverman), MH61675 (D.F. Levinson), and MH60879 (C.R. Cloninger). Further details of collection sites, individuals, and institutions may be found in data supplement Table 1 of Sanders et al. (40) and at the study dbGaP pages.
PY - 2014/3/1
Y1 - 2014/3/1
N2 - Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.
AB - Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.
KW - 7q11.23 duplication syndrome
KW - Autism
KW - Williams-Beuren syndrome
KW - psychiatric genetics
KW - schizophrenia
KW - schizophrenia genetics
UR - https://www.scopus.com/pages/publications/84893798071
UR - https://www.scopus.com/pages/publications/84893798071#tab=citedBy
U2 - 10.1016/j.biopsych.2013.05.040
DO - 10.1016/j.biopsych.2013.05.040
M3 - Article
C2 - 23871472
AN - SCOPUS:84893798071
SN - 0006-3223
VL - 75
SP - 371
EP - 377
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 5
ER -