Meta-analysis of 32 genome-wide linkage studies of schizophrenia

Abstract

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls

“…A substantial body of evidence from family, twin and adoption studies indicated that a genetic component underlies increased risk for schizophrenia, although replications of these results have been elusive (Tsuang et al, 2001;Ng et al, 2009;Purcell et al, 2009;Shi et al, 2009;Stefansson et al, 2009;Sun et al, 2010). These data support the idea that schizophrenia involves many genes interacting with one another and with environmental risk factors (Palha and Goodman, 2006;Ruano et al, 2008;Sun et al, 2010).…”

DISC1 as a Possible Genetic Contribution to Opioid Dependence in a Polish Sample

“…In addition, DISC1 has been reported as a risk factor for some neuropsychiatric phenotypes, such as anxiety, neuroticism, emotional stability, chronic fatigue syndrome, and social anhedonia (Chubb et al, 2008;Thomson et al, 2013). It is important to note that a genome scan meta-analysis, which included 32 independent genome-wide linkage scan analyses, did not provide evidence for linkage between DISC1 and schizophrenia (Ng et al, 2009). Also, a meta-analysis carried out by Mathieson et al (2012) using 10 candidate gene studies and three GWASs did not confirm an association between DISC1 and schizophrenia.…”

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

“…Initially, family-based linkage studies have identified several chromosomal regions and candidate genes that are associated with the risk for schizophrenia [38,39]. However, none of the results of the linkage studies has passed a genome-wide significance level so far [40]. Subsequently, a multitude of association studies that were recently extended by genome-wide association studies (GWAS) identified only a few common variants that contribute a very small increase in the susceptibility for schizophrenia [41][42][43].…”