The inhibitor Pazopanib associated variants do not appear to have any obvious function, and a thorough search for putative functional variants in all coding exons and across intron-exon boundaries revealed no obviously causal variant.64 Another positive GWAS finding in neuropsychiatry is with narcolepsy, a disorder that causes disrupted sleep patterns, with the patient often feeling excessively tired during the day, and
suffering sudden sleep attacks. PreGWAS studies had connected the disorder to an MHC class II antigen called HLA-DQB1*0602, and about 85% of narcoleptics carry this antigen.65 However, there remained unexplained heritability. Very recently, a GWAS study was done on 807 cases and 1074 controls, all positive for HLA-DQB1*0602. Inhibitors,research,lifescience,medical A significant association of three SNPs
in the T cell receptor alpha locus was found, which was then replicated in the same study in 1057 further cases and 1104 controls.66 Further selleck bio analysis showed a single SNP was responsible for the association, although it is not clear whether this variant is itself causal or how it may contribute Inhibitors,research,lifescience,medical to disease. This association is of particular interest because it adds considerable weight to the view that narcolepsy is an autoimmune disease, and as such, it would be the first autoimmune disease to be associated with a T-cell receptor locus. This finding also Inhibitors,research,lifescience,medical opens up the possibility of immunotherapy as a future treatment for narcolepsy. Other neuropsychiatric diseases for which definite, replicated effects of common SNPs have been found include schizophrenia, associated with MHC markers, NRGN and TCF4 Inhibitors,research,lifescience,medical (12 945 cases and 34 591 controls, ORs=1.24, 1.15,1.23),67,68 bipolar disorder, associated with ANK3 and CACNA1C (4 387 cases and 6 209 controls, ORs=1.45 and 1.18) 69, and autism, associated with SNPs at 5p14.1 (3 101 family members, 204 cases and 6 941 controls, OR=1.19).70,71 However, all of these were discovered with very large sample sizes and account for very little of the very high heritability of
these conditions. Rare variants Although studies of common variation in neuropsychiatric disease may be underwhelming, the opposite is true for Inhibitors,research,lifescience,medical rare variation. Although the SNP chips used for GWAS comprise only polymorphisms that are reasonably common (~≥5%), their data can be used Carfilzomib to find other types of non-SNP variants – specifically copy number variants (CNVs) – with much lower frequency. CNVs are duplications or deletions of large stretches of DNA – ranging in size from just a few hundred base pairs to many megabases. To detect such variants, the intensity data from the SNP chips is examined to determine whether particular stretches of SNPs are less intense than expected (or absent), which would indicate a deletion, or more intense than expected, which suggests a duplication.72 Because the CNVs are identified on an individual-by-individual basis, very rare CNVs, even those present in a single individual, can be found.