Polymorphisms in the serotonin transporter gene (5HTT) have been reported to be associated with neuroticism (emotionality) and with depression. A recent report of an association between 5HTT and neuroticism involved unselected samples and self-report questionnaires. We attempted to extend these findings using a selected extremes design and peer ratings. From a sample of 2085 individuals, each assessed on neuroticism by two independent peers, we selected 52 individuals from the top 5% and 54 individuals from the bottom 5%. No association was found for either a functional 44 bp insertion/deletion polymorphism in 5HTT regulatory sequence (5HTTLPR) or for a non-functional variable number tandem repeat 5HTT polymorphism.
Large samples and systematic screens of thousands of DNA markers are needed to detect quantitative trait loci (QTLs) of small effect size. One approach to conduct systematic genome scans for association is to use microarrays which, although expensive and non-reusable, simultaneously genotype thousands of single-nucleotide polymorphisms (SNPs). This brief report provides proof of principle that groups of pooled DNA (for example cases and controls) can be genotyped reliably on a microarray. DNA was pooled for 105 Caucasian males and genotyped three times on microarrays for more than 10,000 SNPs (Affymetrix GeneChip Mapping 10K Array Xba 131). The average correlation was 0.973 between the allele frequency estimates for the three microarrays using the same DNA pool. The correlation was 0.923 between the average of the three microarray estimates using pooled DNA and individual genotyping estimates for a Caucasian population as provided by Affymetrix (NetAffx). Thus, genotyping pooled DNA on microarrays can provide a systematic and powerful approach for identifying QTL associations for complex traits including behavioral dimensions and disorders.
As specific genes are identified that are associated with behavior, it becomes increasingly important for behavioral geneticists to be able to incorporate these genes in their research. Rather than using blood, DNA can be extracted from cheek swabs, which makes it possible to obtain DNA inexpensively by mail from large, widely dispersed individuals. The purpose of this paper is to recommend this technique to the behavioral genetics community and to present results of our use of this technique to obtain DNA by mail for 114 2-year-olds and 116 adults.
Succinate-semialdehyde dehydrogenase (SSADH) deficiency is a rare cause of learning disability. We have investigated SSADH to assess its contribution to cognitive ability in the general population in both case-control-and family-based analyses. Sequence analysis of SSADH revealed four changes affecting the encoded protein, only one of which had a minor allele whose frequency is even moderately common. We genotyped this functional polymorphism in 197 high-IQ cases, 201 average-IQ controls and 196 parent high-IQ offspring trios. The minor allele was significantly less frequent in high-IQ cases and was significantly less frequently transmitted by parents to high-IQ subjects than chance expectation. A previous study has shown that the minor allele encodes a lower activity enzyme than the major allele. These data suggest that higher SSADH activity is associated with higher intelligence across the general population. The effect is small, with each allele having an effect size translating to about 1.5 IQ points.
General cognitive ability (g), which is related to many aspects of brain functioning, is one of the most heritable traits in neuroscience. Similarly to other heritable quantitatively distributed traits, genetic influence on g is likely to be due to the combined action of many genes of small effect [quantitative trait loci (QTLs)], perhaps several on each chromosome. We used DNA pooling for the first time to search a chromosome systematically with a dense map of DNA markers for allelic associations with g. We screened 147 markers on chromosome 4 such that 85% of the chromosome were estimated to be within 1 cM of a marker. Comparing pooled DNA from 51 children of high g and from 51 controls of average g, 11 significant QTL associations emerged. The association with three of these 11 markers ( D4S2943, MSX1 and D4S1607 ) replicated using DNA pooling in independent samples of 50 children of extremely high g and 50 controls. Furthermore, all three associations were confirmed when each individual was genotyped separately ( D4S2943, P = 0. 00045; MSX1, P = 0.011; D4S1607, P = 0.019). Identifying specific genes responsible for such QTL associations will open new windows in cognitive neuroscience through which to observe pathways between genes and learning and memory.
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