Genetic Evidence for a Distinct Subtype of Schizophrenia Characterized by Pervasive Cognitive Deficit

Abstract

A novel phenotyping strategy in schizophrenia, targeting different neurocognitive domains, neurobehavioral features, and selected personality traits, has allowed us to identify a homogeneous familial subtype of the disease, characterized by pervasive neurocognitive deficit. Our genome scan data indicate that this subtype, which accounts for up to 50% of our sample, has a distinct genetic basis and explains linkage to chromosome 6p24 reported previously. If representative of other populations, the ratio of schizophrenia subtypes observed in our families could have a profound impact on sample heterogeneity and on the power of genetic studies to detect linkage and association. Our proposed abbreviated battery of tests should facilitate phenotype characterization for future genetic analyses and allow a focus on a crisply defined schizophrenia subtype, thus promoting a more informed search for susceptibility genes.

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

“…In this regard, a genome-wide scan for intelligence conducted in a general population sample revealed suggestive linkage for IQ on 6p25.3-21.31 and already highlighted NRN1 as a positional candidate gene (Posthuma et al 2005). Moreover, a subtype of schizophrenia characterised by pervasive cognitive deficit was also linked to 6p25-p22 region (Hallmayer et al 2005). More recently, a GWAS has established that common variants (SNPs) may account for 40-50% of intelligence variance (Davies et al 2011) and a GWAS-based pathway analysis has reported that general fluid intelligence appears to be characterised by genes affecting quantity and quality of neurons and therefore neuronal efficiency (Christoforou et al 2014).…”

“…Linkage data have provided positional evidence implicating the short arm of chromosome 6 in the risk for SSD and also in their associated cognitive deficits (Straub et al 1995;Schwab et al 1995;Hallmayer et al 2005). The most studied gene included in this chromosomal region is Dysbindin-1 gene (DTNBP1, 6p22.3), which has been consistently associated with SSD and BPD (Schwab and Wildenauer 2009) as well as with age at onset and cognitive deficits (Wessman et al 2009;FatjoVilas et al 2011).…”

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

“…Firstly, using a cognitive phenotype, two studies have identified linkage to loci on chromosome 6p that are, respectively, overlapping with and adjacent to the dysbindin gene (Hallmayer et al, 2005;Posthuma et al, 2005). Secondly, two recent post-mortem studies have reported specific reductions in the expression of dysbindin in the hippocampal region (Talbot et al, 2004) and the dorsolateral pre-frontal cortex (Weickert et al, 2004) of deceased patients with schizophre-nia.…”

Endophenotypes in psychiatric genetics

“…Further studies have used individual and combined endophenotypes in genetic linkage studies of schizophrenia, although as yet these studies have not resulted in the unambiguous identification of susceptibility genes. [19][20][21] The second use of endophenotypes is to study the functional consequences of risk alleles rather than as a means of identifying novel risk genes. 22 This approach is becoming increasingly popular as evidence for susceptibility genes accumulates since it is perceived as holding much promise for establishing disease mechanisms, for example, by seeking associations of risk alleles with structural or neurocognitive variables.…”

“…In our view, the use of endophenotypes in gene finding, by both linkage and association approaches, is most likely to add value when multiple measures are employed in combination with clinical data. 17,20,24 Putative endophenotypes should be chosen on the basis of robust evidence that they are not only associated with the disease but also that association reflects shared genes (Table 1). Fortunately, increasing attention is now being given to this latter issue.…”