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CNV Roundup: Many Replications, a Few Surprises

17 March 2011. A crop of four recent papers on associations between rare copy number variations (CNVs) and schizophrenia has uncovered new candidate genes and loci—two nearly simultaneous publications drawing on partially overlapping data collections converge on the vasoactive intestinal peptide (VIP) receptor gene VIPR2 at chromosome 7q36, and two papers propose a role for microdeletions at 3q29. Perhaps equally important, the new papers provide strong support for several now-familiar CNVs implicated in the disorder over the past few years (see SRF overview).

CNVs new, CNVs old
Last November, a multicenter team led by David Ledbetter of Emory University School of Medicine (Moreno-De-Luca et al., 2010) reported in the American Journal of Human Genetics that a 1.4-Mb deletion at 17q12 “confers a very high risk” for both autism and schizophrenia. The region, which contains 15 genes, had been tied to autism, “intellectual disability,” and ADHD in a few cases (e.g., Loirat et al., 2010), but in the large combined sample of patients with autism or schizophrenia used in the Ledbetter study (23,271 patients and 52,448 controls), the recurrent deletion was found in 24 cases and no controls, a highly significant association (p = 5 X 10-13).

Patients with the 17q12 deletion also exhibited a distinctive facial phenotype and “mild to moderate intellectual disability.” This chromosomal stretch contains HNF1B, which codes for hepatocyte nuclear factor 1 homeobox B, mutations of which cause renal cysts and diabetes syndrome. However, HNF1B point mutations have not been shown to lead to any other phenotypic features of the 17q12 deletions, suggesting that one or more other genes in this region underlie these. In addition to associating a novel CNV with schizophrenia risk, the paper complements the many recent studies suggesting that autism and schizophrenia have shared genetic origins (see SRF related news story).

An analysis of the Molecular Genetics of Schizophrenia (MGS) dataset combined with two other collections reported online February 1 in the American Journal of Psychiatry by Stanford’s Douglas Levinson and colleagues (Levinson et al., 2011) replicates previous associations of schizophrenia with deletions at chromosomes 1q21.1, 15q13.3, and 22q11.21; duplications at 16p11.2; and various exonic deletions in the neurexin-1 gene that “establish NRXN1 as a specific gene associated with schizophrenia,” say the authors (see SRF related news story).

In addition, the paper attributes schizophrenia risk to a 1.6-Mb deletion at 3q29 spanning 29 genes that has previously been associated with mild mental retardation, microcephaly, and (weakly) with autism, not to mention one schizophrenia patient in a study by Walsh and colleagues in 2008 (see SRF related news story). This dovetails with an August 2010 report in the American Journal of Human Genetics by another Emory team led by Stephen Warren, which completed a GWAS of schizophrenia patients and controls of Ashkenazi Jewish descent and identified an 836-kb deletion at 3q29 associated with schizophrenia (Mulle et al., 2010). The deletion was also present in patients in different follow-up samples, and overall the association generated an odds ratio of 31.5, which the authors say “rivals that of any GWAS of [schizophrenia], and suggests that the 3q29 deletion confers a significant risk for this severe psychiatric phenotype.”

VIP treatment
The Levinson group also found an association between VIPR2 and schizophrenia cases in all three datasets they examined. VIP, which has diverse roles in neural development, response to neural injury, and inflammation, has previously been associated with autism; its close relative, PACAP (pituitary adenylate cyclase-activating polypeptide) has been implicated in schizophrenia (e.g., Matsuzaki and Tohyama, 2008).

VIPR2 is also fingered in a paper published in Nature within weeks of the study by Levinson and colleagues. A team led by Jonathan Sebat of the University of California, San Diego, conducted a two-stage analysis, first identifying 114 regions of interest in a combined sample, then focusing on four loci, employing the same MGS dataset used by the Levinson group. Just as in the Levinson study, structural changes found in three of these regions in schizophrenia patients—deletions at 15q13.3 and 22q11.21, duplications at 16p11.2—added to a growing consensus that genes affected by these CNVs are strongly linked to schizophrenia.

However, in a more novel finding, a number of duplications at 7q36.3 clustered around the VIPR2 gene were seen in 29 cases and only two controls. In their discussion of the gene’s possible role in schizophrenia, Sebat and colleagues focus on VIP’s known functions in the adult brain rather than its neurodevelopmental roles, including regulation of circadian rhythms, neurotransmission, and hippocampal neurogenesis, and the aspects of learning and memory that rely on these last two processes.

VIPR2 codes for VPAC2, a G protein-coupled receptor expressed in a variety of brain regions involved in schizophrenia. VPAC2 binding of VIP initiates cAMP signaling cascades known to be involved in learning and memory. In vitro experiments by the Sebat group suggest that VIPR2 duplications of the sort seen in the CNV significantly increase expression of VIPR2 mRNA, which leads them to propose that schizophrenia patients with 7q36-region mutations may represent a distinct subgroup for whom VPAC2 antagonists could have therapeutic value.

Paths to the clinic, large and small
Levinson and colleagues note that, while it has been hoped that shorter CNVs that affect a small set of candidate genes would be most informative in guiding future research, in their analysis, short CNVs disrupting “obvious” candidate genes had substantially lower odds ratios than longer CNVs, suggesting that it may be precisely the multigenic consequences of these larger CNVs that result in pathology.

At the same time, these authors acknowledge that SNPs and other small mutations may yet be found to have major pathogenic consequences, and they look to whole-genome analyses to help researchers steer between these possibilities.

As CNV replications continue to pile up, however, their clinical relevance also increases, say Levinson and colleagues. “We are reaching the point...where CNV testing could be indicated for individuals with schizophrenia,” they write. “Several strongly associated CNVs have implications for clinical management and pre-conception reproductive counselling of patients.”—Pete Farley.

Levinson DF, Duan J, Oh S, Wang K, Sanders AR, Shi J, Zhang N, Mowry BJ, Olincy A, Amin F, Cloninger CR, Silverman JM, Buccola NG, Byerley WF, Black DW, Kendler KS, Freedman R, Dudbridge F, Pe'er I, Hakonarson H, Bergen SE, Fanous AH, Holmans PA, Gejman PV. Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. Am J Psychiatry. 2011 Mar;168(3):302-16. Abstract

Moreno-De-Luca D; SGENE Consortium, Mulle JG; Simons Simplex Collection Genetics Consortium, Kaminsky EB, Sanders SJ; GeneSTAR, Myers SM, Adam MP, Pakula AT, Eisenhauer NJ, Uhas K, Weik L, Guy L, Care ME, Morel CF, Boni C, Salbert BA, Chandrareddy A, Demmer LA, Chow EW, Surti U, Aradhya S, Pickering DL, Golden DM, Sanger WG, Aston E, Brothman AR, Gliem TJ, Thorland EC, Ackley T, Iyer R, Huang S, Barber JC, Crolla JA, Warren ST, Martin CL, Ledbetter DH. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet. 2010 Nov 12;87(5):618-30. Abstract

Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, Sobreira NL, Valle D, Rudd MK, Satten G, Cutler DJ, Pulver AE, Warren ST. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010 Aug 13;87(2):229-36. Abstract

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, Aquila MD, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, King MC, Karayiorgou M, Levy DL, Delisi LE, Sebat J. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature. 2011 Feb 23. Abstract

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