Population-based linkage analysis of schizophrenia and bipolar case–control cohorts identifies a potential susceptibility locus on 19q13

Abstract

Population-based linkage analysis is a new method for analysing genomewide single nucleotide polymorphism (SNP) genotype data in case-control samples, which does not assume a common disease, common variant model. The genome is scanned for extended segments that show increased identity-by-descent sharing within case-case pairs, relative to case-control or control-control pairs. The method is robust to allelic heterogeneity and is suited to mapping genes which contain multiple, rare susceptibility variants of relatively high penetrance. We analysed genomewide SNP datasets for two schizophrenia case-control cohorts, collected in Aberdeen (461 cases, 459 controls) and Munich (429 cases, 428 controls). Population-based linkage testing must be performed within homogeneous samples and it was therefore necessary to analyse the cohorts separately. Each cohort was first subjected to several procedures to improve genetic homogeneity, including identity-by-state outlier detection and multidimensional scaling analysis. When testing only cases who reported a positive family history of major psychiatric disease, consistent with a model of strongly penetrant susceptibility alleles, we saw a distinct peak on chromosome 19q in both cohorts that appeared in meta-analysis (P = 0.000016) to surpass the traditional level for genomewide significance for complex trait linkage. The linkage signal was also present in a third casecontrol sample for familial bipolar disorder, such that meta-analysing all three datasets together yielded a linkage P = 0.0000026. A model of rare but highly penetrant disease alleles may be more applicable to some instances of major psychiatric diseases than the common disease common variant model, and we therefore suggest that other genome scan datasets are analysed with this new, complementary method.

Genome-wide association study of recurrent major depressive disorder in two European case–control cohorts

“…Substantially, larger samples than the one used in our study would also allow testing the common disease-rare variant hypothesis (CDRV) through direct detection of CNVs as well as through other methods such as the population-based linkage analysis of SNP genotypes. 72 In addition, to fully capture the genetic architecture of MDD the analysis of genes would have to include the interaction with known environmental risk factors for MDD (for example, childhood abuse and stressful life events 71,73,74 ). In summary, considerable hope has relied, and continues to rely on human genetics for improving disease prevention and treatment strategies.…”

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

“…Decreased transporter expression would therefore be expected to reduce glutamate signaling. Interestingly, the human VGLUT1 gene maps to chromosome 19q13, a possible susceptibility locus for schizophrenia (Hamshere et al, 2005;Francks et al, 2010). Furthermore, both VGLUT1 polymorphisms (Shen et al, 2009) and decreased hippocampal VGLUT1 expression have been reported in schizophrenia, particularly in older patients (Eastwood and Harrison, 2005;Sawada et al, 2005;Piyabhan and Reynolds, 2006), where they may contribute to cognitive dysfunction.…”

Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs

“…For example, it is noteworthy that human RyR genes, RYR1 and RYR3, are encoded at sites, 19q13 and 15q14–15, respectively, which have been implicated as risk loci for bipolar disorder in genome-wide association studies (Reif et al, 2004; Francks et al, 2010; Green et al, 2013). Alternatively, these targets may be involved in side effects of ADs such as ventricular tachycardia (Thanacoody and Thomas, 2005; Zima et al, 2008).…”