Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes

Centre for Psychiatry, Barts and the London School of Medicine and Dentistry, London, UK.
Psychiatric genetics (Impact Factor: 1.94). 11/2010; 21(1):1-4. DOI: 10.1097/YPG.0b013e3283413382
Source: PubMed


There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present.
We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample.
Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases.
The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia.

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Available from: Radhika Kandaswamy,
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    • "Family, twin, and adoption studies of BP have shown that there is a substantial genetic component [Edvardsen et al., 2008; Smoller and Finn, 2003], as BP has one of the highest heritability rates of all known psychiatric disorders [McGuffin et al., 2003]. Although there has been a growing number of genome-wide association studies (GWAS) of BP [Baum et al., 2008; Belmonte Mahon et al., 2011; Bergen et al., 2012; Chen et al., 2011; Cichon et al., 2011; Curtis et al., 2011; Djurovic et al., 2010; Ferreira et al., 2008; Goes et al., 2012; Green et al., 2012a; Hattori et al., 2009; Kerner et al., 2011; Lee et al., 2012; Lee et al., 2011; Liu et al., 2011; Meier et al., 2012; Scott et al., 2009; Sklar et al., 2011; Sklar et al., 2008; Smith et al., 2009; Smith et al., 2011; Wang et al., 2010; WTCCC 2007; Yosifova et al., 2011; Zhang et al., 2009], a relatively few number of genome-wide significant single nucleotide polymorphisms (SNPs) have been reported. To date, variants in or near genes DGKH [Baum et al., 2008], CACNA1C [Ferreira et al., 2008; Green et al., 2012b; Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011; Sklar et al., 2011], ANK3 [Chen et al., 2011; Ferreira et al., 2008; Green et al., 2012b; Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011], NCAN [Cichon et al., 2011], ODZ [Green et al., 2012b; Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011; Sklar et al., 2011], TRANK1 [Chen et al., 2011], LMAN2L [Chen et al., 2011], PTGFR [Chen et al., 2011], region 3p21 [Chen et al., 2011], PBAL [Jiang and Zhang, 2011], TRPC4AP [Green et al., 2012b], and between RHEBL1 and DHH [Green et al., 2012b] have reached genome-wide significance for association with BP. "
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    • "In conclusion, the results obtained in this study raise the possibility that microtubule organization and L-type Ca 2+ channels can be studied as effective biomarkers that could help differentiate SZ from BD in addition to their clinical manifestations. In this regard, our results suggest that anomalies in the abovementioned features are robust biomarkers because even in a reduced sample size, significant differences were obtained in both case–control and case–case approaches (Curtis et al., 2011). "
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