Genetics of general cognitive ability

General cognitive ability (g) is a general mental ability to reason, solve problems, comprehend complex ideas, think abstractly, learn quickly and learn from experience. Currently used IQ tests are excellent predictors of g. Heritability estimates for g range between 0.30 and 0.75 making it one of the most heritable human behavioural traits. Many behavioural phenotypes, including g, can be described as complex traits. Inheritance of such traits is governed by a mixture of genetic and environmental factors. Genetic factors contributing to total variance in g are likely to be numerous and additive in nature. In order to identify some of the genetic loci contributing to the total variance in g two approaches were employed. First, a genome-wide association study and second, candidate gene study. Genome-wide association study involved testing 1847 microsatellite markers with an average spacing of 2cM. Markers were initially screened on "original" DNA samples. This was followed by testing all positive findings on an independent "replication" sample set. Only one marker, D4S2460, was significant when all the stages of the study were completed. Investigation of candidate genes involved testing of known Apolipoprotein E (ApoE) promoter polymorphisms and Calcium/calmodulin dependant protein kinase II alpha (CaMKII-a) polymorphisms identified in our laboratories through mutation detection techniques. None of the polymorphisms in either of the two genes showed statistically significant association with a general cognitive ability

Polymorphisms in the phosphate and tensin homolog gene are not associated with late-onset Alzheimer’s disease

The varepsilon4 allele of the APOE locus is the only confirmed risk factor for late-onset Alzheimer's disease (LOAD). The phosphate and tensin homolog (PTEN) gene is both a biological and positional candidate gene for LOAD. Eight polymorphisms spanning this gene were selected from dbSNP and genotyped in pooled DNA samples of both cases and controls. No evidence for association with LOAD was obtained in this study although further investigation revealed low levels of linkage disequlibrium (LD) between the genotyped SNPs. Our results suggest that it is unlikely that genetic variation within the PTEN gene contributes to risk of LOAD

Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder

Aromatic L-amino acid decarboxylase (AADC) is a relatively non specific enzyme involved in the biosynthesis of several classical neurotransmitters including dopamine and 5-hydroxytryptamine (5HT; serotonin).1 AADC does not catalyse the rate limiting step in either pathway, but is rate limiting in the synthesis of 2-phenylethylamine (2PE) which is a positive modulator of dopaminergic transmission and a candidate natural psychotogenic compound.1 We and others have proposed that polymorphism in AADC resulting in altered 2PE activity might contribute to the pathogenesis of psychosis.1,2 In order to test this hypothesis, we have used denaturing high performance liquid chromatography (DHPLC)3 to screen 3943 bases of the aadc gene and its promoter regions for variants that might affect protein structure or expression in 15 unrelated people with schizophrenia, and 15 unrelated people with bipolar disorder. three polymorphisms were identified by dhplc: a insertion/deletion polymorphism in the 5' utr of the neuronal specific mrna (g.-33-30delagag, bases 586-589 of genbank m77828), a t>a variant in the non-neuronal exon 1 (g.-67t>a, genbank m88070), and a g>a polymorphism within intron 8 (g.ivs8 +75g>A, GenBank M84598). Case-control analysis did not suggest that genetic polymorphism in the AADC gene is associated with liability for developing schizophrenia or bipolar disorder

Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease

Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al. (2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples

Candidate gene association studies of the alpha4 (CHRNA4) and beta2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease

Consistent deficits in the cholinergic system are evident in Alzheimer's disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio = 0.57, 95% confidence interval = 0.35-0.95, P = 0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio = 0.70, 95% confidence interval = 0.52-0.95, P = 0.019). These data suggest that this variant warrants further examination in large case-control series. (C) 2004 Elsevier Ireland Ltd. All rights reserved