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Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, Iakoucheva LM, Krastoshevsky O, Krause V, Larach-Walters V, Welsh DK, Craig D, Kelsoe JR, Gershon ES, Leal SM, Dell Aquila M, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, King MC, Karayiorgou M, Levy DL, DeLisi LE, Sebat J - Nature (2011)

Bottom Line: Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample.All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2.VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3.

View Article: PubMed Central - PubMed

Affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 12824, USA.

ABSTRACT
Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

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Detection and validation of microduplications and triplications of 7q36.3a) Map of CNVs detected in the primary and secondary cohorts from the UCSC genome browser. (b) Plots of probe intensity ratios for 16 CNVs detected in the primary and MGS datasets. All are cases, with the exception of two controls, who are indicated with an asterisk*. Regions with estimated copy numbers of 2, 3 and 4 are highlighted in gray, blue and green, respectively. Locations of four Sequenom validation assays are shown (dashed lines). (c-f) CNV genotypes were confirmed by MeZOD cluster plots of probe intensity ratios of the proximal and distal regions and in the primary dataset (c and d, respectively) and secondary dataset (e and f, respectively). Absolute copy numbers were confirmed for duplications and triplications of the proximal (g) and distal (h) regions by Sequenom MASSarray genotyping.
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Figure 1: Detection and validation of microduplications and triplications of 7q36.3a) Map of CNVs detected in the primary and secondary cohorts from the UCSC genome browser. (b) Plots of probe intensity ratios for 16 CNVs detected in the primary and MGS datasets. All are cases, with the exception of two controls, who are indicated with an asterisk*. Regions with estimated copy numbers of 2, 3 and 4 are highlighted in gray, blue and green, respectively. Locations of four Sequenom validation assays are shown (dashed lines). (c-f) CNV genotypes were confirmed by MeZOD cluster plots of probe intensity ratios of the proximal and distal regions and in the primary dataset (c and d, respectively) and secondary dataset (e and f, respectively). Absolute copy numbers were confirmed for duplications and triplications of the proximal (g) and distal (h) regions by Sequenom MASSarray genotyping.

Mentions: 15q13.3, 16p11.2 and 22q11.2 are well-documented loci conferring increased risk for schizophrenia 2,5,8. All are hotspots for non-allelic homologous recombination (NAHR), and all alleles contributing to the association consist of large deletions with similar breakpoints. By contrast, microduplications at 7q36.3 have not been previously implicated in neuropsychiatric disorders. The 7q36.3 region harbored CNVs that overlapped but differed in size and breakpoint positions (Fig. 1a). The peak of association is located in the subtelomeric region of 7q, upstream of the gene VIPR2. Also, ranking fifth among the associations genome-wide was another region, 125 kb proximal to the peak at 7q36.3 (P = 0.0007, Table 1). Combining the two 7q36.3 regions into a single 362 kb region (chr7:158,448,321-158,810,016), duplications were detected in 29 of 8,290 (0.35%) patients and 2 of 7,431 (0.03%) controls in this study. The p-value for the combined region in the combined sample was 5.7×10-7 and the OR was 14.1 [3.5, 123.9]. A complete list of 7q36.3 CNVs is provided in Supplementary Table 3.


Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.

Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, Iakoucheva LM, Krastoshevsky O, Krause V, Larach-Walters V, Welsh DK, Craig D, Kelsoe JR, Gershon ES, Leal SM, Dell Aquila M, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, King MC, Karayiorgou M, Levy DL, DeLisi LE, Sebat J - Nature (2011)

Detection and validation of microduplications and triplications of 7q36.3a) Map of CNVs detected in the primary and secondary cohorts from the UCSC genome browser. (b) Plots of probe intensity ratios for 16 CNVs detected in the primary and MGS datasets. All are cases, with the exception of two controls, who are indicated with an asterisk*. Regions with estimated copy numbers of 2, 3 and 4 are highlighted in gray, blue and green, respectively. Locations of four Sequenom validation assays are shown (dashed lines). (c-f) CNV genotypes were confirmed by MeZOD cluster plots of probe intensity ratios of the proximal and distal regions and in the primary dataset (c and d, respectively) and secondary dataset (e and f, respectively). Absolute copy numbers were confirmed for duplications and triplications of the proximal (g) and distal (h) regions by Sequenom MASSarray genotyping.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3351382&req=5

Figure 1: Detection and validation of microduplications and triplications of 7q36.3a) Map of CNVs detected in the primary and secondary cohorts from the UCSC genome browser. (b) Plots of probe intensity ratios for 16 CNVs detected in the primary and MGS datasets. All are cases, with the exception of two controls, who are indicated with an asterisk*. Regions with estimated copy numbers of 2, 3 and 4 are highlighted in gray, blue and green, respectively. Locations of four Sequenom validation assays are shown (dashed lines). (c-f) CNV genotypes were confirmed by MeZOD cluster plots of probe intensity ratios of the proximal and distal regions and in the primary dataset (c and d, respectively) and secondary dataset (e and f, respectively). Absolute copy numbers were confirmed for duplications and triplications of the proximal (g) and distal (h) regions by Sequenom MASSarray genotyping.
Mentions: 15q13.3, 16p11.2 and 22q11.2 are well-documented loci conferring increased risk for schizophrenia 2,5,8. All are hotspots for non-allelic homologous recombination (NAHR), and all alleles contributing to the association consist of large deletions with similar breakpoints. By contrast, microduplications at 7q36.3 have not been previously implicated in neuropsychiatric disorders. The 7q36.3 region harbored CNVs that overlapped but differed in size and breakpoint positions (Fig. 1a). The peak of association is located in the subtelomeric region of 7q, upstream of the gene VIPR2. Also, ranking fifth among the associations genome-wide was another region, 125 kb proximal to the peak at 7q36.3 (P = 0.0007, Table 1). Combining the two 7q36.3 regions into a single 362 kb region (chr7:158,448,321-158,810,016), duplications were detected in 29 of 8,290 (0.35%) patients and 2 of 7,431 (0.03%) controls in this study. The p-value for the combined region in the combined sample was 5.7×10-7 and the OR was 14.1 [3.5, 123.9]. A complete list of 7q36.3 CNVs is provided in Supplementary Table 3.

Bottom Line: Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample.All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2.VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3.

View Article: PubMed Central - PubMed

Affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 12824, USA.

ABSTRACT
Rare copy number variants (CNVs) have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large (>500-kilobase) CNVs at several loci, including microdeletions at 1q21.1 (ref. 2), 3q29 (ref. 3), 15q13.3 (ref. 2) and 22q11.2 (ref. 4) and microduplication at 16p11.2 (ref. 5). However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 (0.35%) patients versus 2 of 7,431 (0.03%) controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs.

Show MeSH
Related in: MedlinePlus