Badner and Gershon (2001) presented a technique of meta-analysis of linkage data that could be applied to published genome scans. It combines the reported P-values of individual studies, after correcting each value for the size of the region containing a minimum P-value. Simulations demonstrated that the type I error rate was at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied. Power to detect linkage was at least as high as the power of pooling the data from all the studies. We applied this method to all the published genome scans for bipolar disorder and schizophrenia. We found the strongest evidence for susceptibility loci on 13q (P < 6 x 10(-6)) and 22q (P < 1 x 10(-5)) for bipolar disorder, and on 8p (P < 2 x 10(-4)), 13q (P < 7 x 10(-5)), and 22q (P < 9 x 10(-5)) for schizophrenia.

Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

Wolfram syndrome (WFS; OMIM 222300) is an autosomal recessive neurodegenerative disorder defined by young-onset non-immune insulin-dependent diabetes mellitus and progressive optic atrophy. Linkage to markers on chromosome 4p was confirmed in five families. On the basis of meiotic recombinants and disease-associated haplotypes, the WFS gene was localized to a BAC/P1 contig of less than 250 kb. Mutations in a novel gene (WFS1) encoding a putative transmembrane protein were found in all affected individuals in six WFS families, and these mutations were associated with the disease phenotype. WFS1 appears to function in survival of islet s-cells and neurons.

A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)

The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 × 10−8, experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder.

Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24–22, 1q21–22, and 13q32–34, while other promising regions include 8p21–22, 6q16–25, 22q11–12, 5q21–q33, 10p15–p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16–q22, 12q23–q24, and regions of 9p22–p21, 10q21–q22, 14q24–q32, 13q32–q34, 22q11–q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.

https://jmg.bmj.com/content/jmedgenet/42/3/193.full.pdf

The genetics of schizophrenia and bipolar disorder: dissecting psychosis

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

/pdf/genome-scan-meta-analysis-of-schizophrenia-and-bipolar-tfjm1qitkb.pdf

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

The main clinical feature of bipolar affective disorder is a change of mood to depression or elation. Unipolar disorder, also termed major depressive disorder, describes the occurrence of depression alone without episodes of elevated mood. Little is understood about the underlying causes of these common and severe illnesses which have estimated lifetime prevalences in the region of 0.8% for bipolar and 6% for unipolar disorder. Strong support for a genetic aetiology is found in the familial nature of the condition, the increased concordance of monozygotic over dizygotic twins and adoption studies showing increased rates of illness in children of affected parents. However, linkage studies have met with mixed success. An initial report of linkage on the short arm of chromosome 11 (ref. 4) was revised and remains unreplicated. Reports proposing cosegregation of genes found on the X chromosome with bipolar illness have not been supported by others. More recently bipolar disorder has been reported to be linked with markers on chromosomes 18, 21, 16 and a region on the X chromosome different from those previously suggested. We have carried out a linkage study in twelve bipolar families. In a single family a genome search employing 193 markers indicated linkage on chromosome 4p where the marker D4S394 generated a two-point lod score of 4.1 under a dominant model of inheritance. Three point analyses with neighbouring markers gave a maximum lod score of 4.8. Eleven other bipolar families were typed using D4S394 and in all families combined there was evidence of linkage with heterogeneity with a maximum two-point lod score of 4.1 (theta = 0, alpha = 0.35).

A locus for bipolar affective disorder on chromosome 4p

Following the description of linkage of markers at chromosome 4p16 to bipolar disorder in several families [Blackwood et al., 1996], and the association of the alleles of a polymorphism closely linked to D5 dopamine receptor gene with schizophrenia [Williams et al., 1997], we have looked for linkage disequilibrium between a series of microsatellite markers from this region and major psychoses including schizophrenia, bipolar disorder, and unipolar major depressive disorder. A significant increase in the frequency of the 148 bp allele of DRD5 (P = 0.024) and the 244 bp allele of D4S615 (P = 0.001) was found in patients with schizophrenia (n = 158 DRD5; n = 133 D4S615), compared with patients with bipolar disorder (n = 270 DRD5; n = 107 D4S615), or controls without psychiatric illness (n = 437 DRD5; n = 309 D4S615). The frequency of the 148 bp allele of DRD5 was also increased in schizophrenia over unipolar major depressive disorder (n = 65). D4S615 was not typed in unipolar disorder. The estimated odds ratios confirmed that the 148 bp allele of DRD5 and the 244 bp allele of D4S615 conferred increased risk of schizophrenia. Estimated Haplotype (EH) analysis of 174 controls and 128 patients with schizophrenia who were typed for both markers confirmed the strong associations with these alleles but did not show evidence that the markers were in linkage disequilibrium with each other even though they lie approximately 150 kb apart. The data are consistent with an association between markers close to the D5 dopamine receptor and schizophrenia, but not bipolar disorder or unipolar major depression.

Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder.

An improved protocol has been developed for physical enrichment of cDNA sequences by hybridization to genomic DNA. When applied to microdissection recombinants derived from a translocation breakpoint region associated with inherited mental illness, a single cycle of the procedure permitted enriched cDNAs to be visualized directly by agarose gel electrophoresis. Hybridization screening of a library of clones derived from the enriched cDNAs, employing the genomic resource as a probe, led to the identification of six novel gene fragments. This general approach to the isolation of regionally encoded genes could be applied to any subchromosomal interval as a first step towards global transcription map construction.

Identifying genes within microdissected genomic DNA: Isolation of brain expressed genes from a translocation region associated with inherited mental illness

M.L. Thomson

Papers

A locus for bipolar affective disorder on chromosome 4p

Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder.

Identifying genes within microdissected genomic DNA: Isolation of brain expressed genes from a translocation region associated with inherited mental illness