Single Nucleotide Variation Analysis in 65 Candidate Genes for CNS Disorders in a Representative Sample of the European Population

Abstract

The detailed investigation of variation in functionally important regions of the human genome is expected to promote understanding of genetically complex diseases. We resequenced 65 candidate genes for CNS disorders in an average of 85 European individuals. The minor allele frequency (MAF), an indicator of weak purifying selection, was lowest in radical amino acid alterations, whereas similar MAF was observed for synonymous variants and conservative amino acid alterations. In noncoding sequences, variants located in CpG islands tended to have a lower MAF than those outside CpG islands. The transition/transversion ratio was increased among both synonymous and conservative variants compared with noncoding variants. Conversely, the transition/transversion ratio was lowest among radical amino acid alterations. Furthermore, among nonsynonymous variants, transversions displayed lower MAF than did transitions. This suggests that transversions are associated with functionally important amino acid alterations. By comparing our data with public SNP databases, we found that variants with lower allele frequency are underrepresented in these databases. Therefore, radical variants obtain distinctively lower database coverage. However, those variants appear to be under weak purifying selection and thus could play a role in the etiology of genetically complex diseases.

Systematic investigation of genetic variability in 111 human genes—implications for studying variable drug response

“…As described earlier, 5 MAF differed significantly between synonymous SNPs (MAF ¼ 12.0%, n ¼ 143), conservative amino-acid alterations (MAF ¼ 8.3%, n ¼ 105) and radical amino-acid alterations (MAF ¼ 4.7%, n ¼ 26) (P ¼ 0.001, Kruskal-Wallis H test). When analyzing the 453 noncoding SNPs, we found MAF of SNPs located in regions annotated as highly conserved (either mouse or rat or both) (MAF ¼ 11.2%, n ¼ 119) significantly lower than MAF of noncoding SNPs not located in such highly conserved regions (MAF ¼ 14.0%, n ¼ 334) (P ¼ 0.001, two-sided Mann-Whitney U test).…”

“…Previous large-scale resequencing studies 4,5,8,9 found lower nucleotide diversity for coding regions compared to noncoding regions and decreased allele frequency for coding SNPs. These findings can be explained by the influence of purifying selection on nucleotide diversity in the human genome.…”

“…5 This evaluation was based on dbSNP build 112, released on 21 March 2003, containing 3 741 182 human SNPs. At that time, 159 (41%) of a total of 388 identified SNPs were known as polymorphic sites to dbSNP, the coverage rate was high (80%) for highly frequent variants (MAFZ20%) and only 20% for rare variants (MAFo5% except singletons).…”

“…It has been shown that rare variants are more likely to have potential functional significance. [4][5][6] Lowfrequency functional variants in particular may account for severe adverse reactions to medication. Although these severe adverse reactions are relatively rare, at least 100 000 deaths per year in the United States alone are attributed to adverse reactions to prescription drugs.…”

“…7 Unfortunately, SNP databases show a strong under-representation of rare variants. 5 This is not surprising since the chance of detecting a variant on a limited number of chromosomes correlates with its population frequency. Consequently, focused resequencing in larger samples of individuals is necessary to systematically identify low-frequency variants.…”