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Copy-number Variants, Interacting Alleles, or Both?

10 February 2009. Studies from two international research teams suggest different ways around the seemingly messy findings on genetic influences in schizophrenia. One points to common single-nucleotide changes in the DNA, the other to larger, rarer mutations. The group led by Jesper Ekelund of the National Public Health Institute in Helsinki, Finland, connects a dampened ability to enjoy social interactions, a schizophrenia hallmark, to variants in the DISC1 gene, acting alone and in concert. In contrast, findings from David Goldstein of Duke University in Durham, North Carolina, and his team discount the role of single-nucleotide polymorphisms (SNPs) in schizophrenia, but build a case for an influence of big missing chunks of DNA.

Time to end the focus on SNPs?
Over the years, researchers have fingered various genes and SNPs as influencing the risk of schizophrenia, but emerging evidence also suggests that deletions, disruptions, or duplications of the genome—copy-number variants (CNVs)—may foster the disease (see SRF related news story; SRF related news story). Prior studies have focused on either SNPs or CNVs, but a report in the February PLoS Genetics takes a genome-wide look at the role both might play in schizophrenia.

The researchers, including first author Anna Need of Duke University, sought to correct two perceived shortcomings of prior research. First, SNP studies have lacked enough power to reliably detect associations, according to many commentators. Second, while past research suggests a role of rare, highly penetrant CNVs in schizophrenia, it has ignored the possible involvement of common CNVs, according to Need and colleagues.

Need and colleagues first tried to uncover schizophrenia-related SNPs by comparing 871 patients with 863 unaffected control subjects. They discerned no consistent genome-wide associations with the disease. Just to make sure, they pursued the top 100 hits in four cohorts with a total of 1,460 patients and 12,995 controls, all of European stock. They again found no clear support for a role of any SNP in schizophrenia, contrary to past genome-wide association and candidate gene studies.

The research group also examined CNVs in a subset of 1,013 patients with schizophrenia and 1,084 healthy controls of European descent from three cohorts, plus 60 patients and 64 controls of African lineage. Prior studies disagree on whether patients with schizophrenia are more likely than control subjects to carry rare CNVs greater than 100 kb that disrupt genes or delete or copy whole genes. The new study found no clear excess of these in schizophrenia.

The story looked different when Need and colleagues examined larger CNVs involving more than 2 Mb. Deletions of this size occurred in eight patients with schizophrenia and none of the controls, which included not only the European and African CNV cohorts but also 1,547 healthy, cognitively normal subjects of mixed ethnicity. Four of these deletions appeared in chromosome region 22q11.2, bolstering evidence that it contributes to schizophrenia (see SRF related news story). In addition, they found one deletion on 16p13.11-p12.4, a segment that harbors the gene NDE1, a binding partner of DISC1 (see SRF related news story). Another, on 8p22, contains schizophrenia candidate genes fingered in prior studies, including one that encodes PCM1 (see SRF related news story); however, support for this CNV’s role in schizophrenia came from only one of the cohorts in the new study.

When the researchers examined common CNVs in the cohorts of European heritage, they could not consistently tie any to schizophrenia, although they acknowledge that the genotyping platforms they used can miss common CNVs. Therefore, they write, “it is not possible for us to conclusively rule out effects of common CNVs on schizophrenia.”

According to Need and colleagues, the findings “support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms.” However infrequent a given mutation may be, they hope that some of them will point to a common pathway amenable to treatment. They write, “We conclude that schizophrenia genetics research must turn sharply toward the identification of rare genetic contributors and that the most important tool in this effort will be complete whole-genome sequencing of patients whose clinical characteristics have been very thoroughly assessed.”

Despite their results, the researchers do not entirely dismiss SNPs. To the contrary, they suggest that the difficulty in producing reliable SNP findings could stem from interactions among genetic variants.

Interplay among DISC1 SNPs
Potential interactions, as well as solo effects, of DISC1 variants on endophenotypes tied to schizophrenia comprised the focus of a study in this month’s Archives of General Psychiatry. First author Liisa Tomppo, of the National Public Institute in Helsinki, and colleagues contend that researchers seeking genetic risk factors for schizophrenia need to think beyond the usual studies of at-risk families and unrelated people with schizophrenia. Therefore, they investigated whether variants in DISC1, the disrupted-in-schizophrenia 1 gene, raise the risk of developing psychosis-related traits among the general population.

DISC1, a prime suspect in the schizophrenia gene lineup, seems to contribute to positive and negative symptoms in schizophrenia (see SRF related news story and SRF live discussion). It also appears to influence cognition in both healthy and patient populations (see review by Porteous et al., 2006).

The study’s subjects came from a birth cohort that included nearly everyone born in a region in Finland in 1966; 39 percent of the original group, or 4,651 subjects, participated in a 31-year follow-up and were included in the study. To prevent diagnosis or treatment from confounding the results, the researchers excluded 124 people who had been diagnosed or treated for a psychiatric disorder between 1982 and 1997.

The researchers assessed traits that echo those seen in psychosis—specifically perceptual abnormalities, a decreased capacity to feel physical pleasure, a reduced ability to enjoy social contact, and schizotypic personality features. They measured these intermediate phenotypes using four questionnaires: the Perceptual Aberration Scale, the Revised Social Anhedonia Scale, the Revised Physical Anhedonia Scale, and the Schizoidia Scale.

Based on past research, Tomppo and colleagues chose 41 SNPs in the DISC1-TSNAX region of chromosome 1 to examine. After adjusting for the number of tests performed, they found higher social anhedonia in carriers of the minor allele of marker rs821577. Separate analyses in men and women showed that the association in women drove this finding. The investigators also tied two other markers, rs11122381 and rs821592, to this trait in women only.

A case-control study (Hennah et al., 2008) previously found that a minor allele of rs821633 increased schizophrenia risk by itself and in combination with the minor alleles of markers rs1538979 and rs821577; in the absence of those two alleles, it guarded against the disease. Tomppo’s team sought to extend these findings to traits that reflect psychosis liability in the general population. Although they could not replicate the solo effect of SNP rs821633, they did tie interplay among the same three alleles to social and physical anhedonia, in the entire sample and in women specifically. In addition, their findings regarding rs821577 mirrored those involving bipolar disorder in the earlier study.

According to the researchers, “These findings support a role of DISC1 in regulating the level of psychosis proneness in the general population.” They further suggest that “DISC1 might be more central to human psychological functioning than previously thought, as it seems to affect the degree to which people enjoy social interactions.” Eventually, it may bridge our understanding of schizophrenia and other disorders characterized by social isolation, such as autism and affective disorders.—Victoria L. Wilcox.

Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperaviciute D, Gennarelli M, Strittmatter WJ, Bonvicini C, Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RSE, Fisher EMC, St. Jean PL, Giegling I, Hartmann AM, Möller H-J, Ruppert A, Fraser G, Crombie C, Middleton LT, St. Clair D, Roses AD, Muglia P, Francks C, Rujescu D, Meltzer HY, Goldstein DB. A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genet. 2009 Feb;5(2):e1000373. Abstract

Tomppo L, Hennah W, Miettunen J, Järvelin M-R, Veijola J, Ripatti S, Lahermo P, Lichtermann D, Peltonen L, Ekelund J. Association of variants in DISC1 with psychosis-related traits in a large population cohort. Arch Gen Psychiatry. 2009 Feb;66(2):134-141. Abstract

Comments on News and Primary Papers
Comment by:  David J. Porteous, SRF Advisor
Submitted 11 February 2009 Posted 12 February 2009

The answer is unequivocally, “yes”
In...  Read more

View all comments by David J. Porteous

Comment by:  Pamela DeRosseAnil Malhotra (SRF Advisor)
Submitted 19 February 2009 Posted 22 February 2009

The results reported by Tomppo et al. and Need et al....  Read more

View all comments by Pamela DeRosse
View all comments by Anil Malhotra

Comment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 25 February 2009 Posted 25 February 2009

Has anyone considered the possibility that the CNVs found...  Read more

View all comments by James L. Kennedy

Comment by:  Kevin J. Mitchell
Submitted 2 March 2009 Posted 2 March 2009

The papers by Need et al. and Tomppo et al. seem to...  Read more

View all comments by Kevin J. Mitchell
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