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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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Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cyclic-AMP signaling(a) Quantitative PCR results of VIPR2 mRNA from lymphoblastoid cell lines. Two to four subjects were tested for each of four genotypes (subtelomeric duplication, VIPR2 duplication, exon 3/4 triplication, and normal diploid copy number as control). Results are expressed as the mean fold-change of CNV carriers relative to the mean of control samples. (b-c) Cyclic AMP accumulation was measured in the same cell lines in response to VIP (100nM) and the VPAC2 agonist BAY 55-9837 (100nM). Results are expressed as fold-change over forskolin/IBMX alone. (d) No significant differences were observed in cAMP response to another GPCR agonist, Prostaglandin E2 (PGE2, 1 μM), demonstrating that the effects are specific to VPAC2. For subjects, error bars represent standard error of the mean computed across replicates. Differences between the groups of 9 duplication carriers and 4 controls were tested using unpaired two sample t-tests.
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Figure 3: Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cyclic-AMP signaling(a) Quantitative PCR results of VIPR2 mRNA from lymphoblastoid cell lines. Two to four subjects were tested for each of four genotypes (subtelomeric duplication, VIPR2 duplication, exon 3/4 triplication, and normal diploid copy number as control). Results are expressed as the mean fold-change of CNV carriers relative to the mean of control samples. (b-c) Cyclic AMP accumulation was measured in the same cell lines in response to VIP (100nM) and the VPAC2 agonist BAY 55-9837 (100nM). Results are expressed as fold-change over forskolin/IBMX alone. (d) No significant differences were observed in cAMP response to another GPCR agonist, Prostaglandin E2 (PGE2, 1 μM), demonstrating that the effects are specific to VPAC2. For subjects, error bars represent standard error of the mean computed across replicates. Differences between the groups of 9 duplication carriers and 4 controls were tested using unpaired two sample t-tests.

Mentions: Cyclic-AMP signaling has been implicated in schizophrenia 22,23. We hypothesized that increases in VIPR2 transcription and VPAC2-mediated cAMP signaling would be a consequence of the microduplications at 7q36.3. We thus assessed VIPR2 mRNA and cAMP accumulation in response to VIP and a VPAC2-selective agonist (BAY 55-9837) in lymphoblastoid cell lines from eight MGS study subjects: two with subtelomeric duplications, three with duplications of VIPR2, four with partial triplications, and four controls with normal copy number of the region (see Supplementary Note). VIPR2 transcripts were present at low but measurable levels in all cell lines. VIPR2 mRNA levels were significantly increased in duplication carriers compared with controls (Fig. 3a). Likewise, cAMP responses to VIP and BAY 55-9837 were significantly greater in lymphoblastoid lines from carriers as compared to controls (Fig. 3b). In contrast, we observed no group difference in cAMP accumulation in response to a different GPCR agonist, prostaglandin E2, thus confirming that the effect of 7q36 duplications on cAMP accumulation is mediated by VPAC2R.


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)

Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cyclic-AMP signaling(a) Quantitative PCR results of VIPR2 mRNA from lymphoblastoid cell lines. Two to four subjects were tested for each of four genotypes (subtelomeric duplication, VIPR2 duplication, exon 3/4 triplication, and normal diploid copy number as control). Results are expressed as the mean fold-change of CNV carriers relative to the mean of control samples. (b-c) Cyclic AMP accumulation was measured in the same cell lines in response to VIP (100nM) and the VPAC2 agonist BAY 55-9837 (100nM). Results are expressed as fold-change over forskolin/IBMX alone. (d) No significant differences were observed in cAMP response to another GPCR agonist, Prostaglandin E2 (PGE2, 1 μM), demonstrating that the effects are specific to VPAC2. For subjects, error bars represent standard error of the mean computed across replicates. Differences between the groups of 9 duplication carriers and 4 controls were tested using unpaired two sample t-tests.
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Related In: Results  -  Collection

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Figure 3: Duplications and triplications of 7q36.3 result in increased VIPR2 transcription and cyclic-AMP signaling(a) Quantitative PCR results of VIPR2 mRNA from lymphoblastoid cell lines. Two to four subjects were tested for each of four genotypes (subtelomeric duplication, VIPR2 duplication, exon 3/4 triplication, and normal diploid copy number as control). Results are expressed as the mean fold-change of CNV carriers relative to the mean of control samples. (b-c) Cyclic AMP accumulation was measured in the same cell lines in response to VIP (100nM) and the VPAC2 agonist BAY 55-9837 (100nM). Results are expressed as fold-change over forskolin/IBMX alone. (d) No significant differences were observed in cAMP response to another GPCR agonist, Prostaglandin E2 (PGE2, 1 μM), demonstrating that the effects are specific to VPAC2. For subjects, error bars represent standard error of the mean computed across replicates. Differences between the groups of 9 duplication carriers and 4 controls were tested using unpaired two sample t-tests.
Mentions: Cyclic-AMP signaling has been implicated in schizophrenia 22,23. We hypothesized that increases in VIPR2 transcription and VPAC2-mediated cAMP signaling would be a consequence of the microduplications at 7q36.3. We thus assessed VIPR2 mRNA and cAMP accumulation in response to VIP and a VPAC2-selective agonist (BAY 55-9837) in lymphoblastoid cell lines from eight MGS study subjects: two with subtelomeric duplications, three with duplications of VIPR2, four with partial triplications, and four controls with normal copy number of the region (see Supplementary Note). VIPR2 transcripts were present at low but measurable levels in all cell lines. VIPR2 mRNA levels were significantly increased in duplication carriers compared with controls (Fig. 3a). Likewise, cAMP responses to VIP and BAY 55-9837 were significantly greater in lymphoblastoid lines from carriers as compared to controls (Fig. 3b). In contrast, we observed no group difference in cAMP accumulation in response to a different GPCR agonist, prostaglandin E2, thus confirming that the effect of 7q36 duplications on cAMP accumulation is mediated by VPAC2R.

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