Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24

Abstract

is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P ¼ 0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P ¼ 0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P ¼ 0.0008; heterogeneity LOD score, dominant model 2.65, a ¼ 0.82). Additionally, NPL scores 42.0 were observed at chromosome 2q37, 4p15-16, 7p22, 9q21-22 and 14q11.1-11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21-22.

The trace amine receptor 4 gene is not associated with schizophrenia in a sample linked to chromosome 6q23

“…These analyses (details available on request) indicated that our sample has a power (1Àb) X80%, with the exception of cases where the GenAF is lower than 0.15. Allelic stratification is unlikely in our homogeneous population, and the previous results from linkage analyses in our population 8,9 render estimates for a GenAF < 0.2 improbable. Nevertheless, the power to detect a positive association holds if the association is present only in 40% of the sample for a gene showing a GenAF X0.2.…”

“…8,9 Our peak linkage was at 136.3 Mb rendering TRAR4 (at 132.9 Mb) a viable positional candidate. In fact, TRAR4 is considerably closer to the linkage peak in our sample than to the more diffuse signal observed in the samples found to be associated with TRAR4.…”

“…8 Fine mapping led to an increase of the NPL to 4.98 (P = 0.00000058) 9 and reduced the putative susceptibility region (NPL-1) to 3.90 Mb. Therefore, it was highly pertinent to determine whether association with TRAR4 could be replicated in our sample.…”

“…8,9 The project was approved by the Internal Review Board of the Hadassah-Hebrew University Medical Center and written informed consent was obtained from all subjects. Including families recruited subsequent to the genome scan, our sample consisted of 53 families (190 individuals with DNA, 85 affected; 34 'triad' families and 19 families with two or more affected offspring).…”

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia

“…5 A number of other groups have found evidence of linkage of BPAD and/or SCZ to this 4p region as well. Asherson et al 6 reported linkage in a schizoaffective family (F50, LOD = 2.0); Ewald et al 7 reported linkage in BPAD families (LOD = 2.0); Detera-Wadleigh et al 8 investigated families with major mental illness, and their largest family (F48) generated an LOD of 3.2; Williams et al 9 found increased sharing in SCZ sibpairs (LOD = 1.7); Lerer et al 10 found a non-parametric LOD score of 2.2 in families with SCZ and schizoaffective disorder; and Als et al 11 found excess haplotype sharing (best P-value, P = 0.00007) in families with BPAD and SCZ.…”