BackgroundA number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.AimsTo determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia (n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.MethodWe used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.ResultsWe found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader-Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia (P<4.1×10–4).ConclusionsWe strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.

Complex multicellular organisms, such as mammals, express two complete sets of chromosomes per nucleus, combining the genetic material of both parents. However, epigenetic studies have demonstrated violations to this rule that are necessary for mammalian physiology; the most notable parental allele expression phenomenon is genomic imprinting. With the identification of endogenous imprinted genes, genomic imprinting became well-established as an epigenetic mechanism in which the expression pattern of a parental allele influences phenotypic expression. The expanding study of genomic imprinting is revealing a significant impact on brain functions and associated diseases. Here, we review key milestones in the field of imprinting and discuss mechanisms and systems in which imprinted genes exert a significant role.

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also post-natal functions including energy homeostasis2 and behaviour3, 4. When the two parental alleles are unequally represented within a social group (when there is sex-bias in dispersal and/or variance in reproductive success)5, 6, imprinted genes may evolve to modulate social behaviour, although to date no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adapter protein that can interact with a number of receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10 deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus, Grb10 is to date a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, due to actions of the two parental alleles in different tissues.

In a small fraction of mammalian genes--at present estimated at less than 1% of the total--one of the two alleles that is inherited by the offspring is partially or completely switched off. The decision as to which one is silenced depends on which allele was inherited from the mother and which from the father. These idiosyncratic loci are known as imprinted genes, and their existence is an evolutionary enigma, as they effectively nullify the advantages of diploidy. Although they are small in number, these genes have important effects on physiology and behaviour, and many are expressed in the brain. There is increasing evidence that imprinted genes influence brain function and behaviour by affecting neurodevelopmental processes.

Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.