From Rare Mutations to Normal Variation: Genetic Association Study of Mathematical, Spatial, and General Cognitive Abilities

Background. Behavioral genetic fndings suggest that complex traits, such as mathemat-ical ability, general cognitive ability (intelligence; g), and spatial ability, are infuenced by many common genetic variants of very small efects that operate across the ability continuum. Common genetic variants may also be responsible for cognitive defcits as-sociated with rare genetic syndromes, in which whole genomic regions may be afected. To date, relatively few common genetic variants involved in cognitive traits have been identifed, and these only explain a small proportion of variance in these traits. Objective. Te aim of the study was to fnd associations between mathematics-re-lated traits and single-nucleotide polymorphisms (SNPs) within chromosomal regions involved in Williams and Prader-Willi disorders. Both disorders are characterized by patterns of weaknesses and strengths in cognitive abilities. Two types of analyses were performed (SNP-based and gene-based), using genotypic and phenotypic data available for 3000 participants from the UK. Results. SNP-based tests indicated that none of the SNPs passed the demanding multiple testing correction level for any of the phenotypes. Gene-based analysis sug-gested that 2 pseudogenes (i.e., GOLGA8I and WHAMMP3) were signifcantly asso-ciated with intelligence, and 1 gene (i.e., TUBGCP5) was signifcantly associated with mathematics at 16 years of age. Conclusion. Te results are consistent with other fndings demonstrating that cog-nitive traits are infuenced by many common genetic variants with very small efects. The results also suggest that a small number of these variants may be located in the chromo-somal regions afected in Prader-Willi and Williams syndrome regions

Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis

Extent: 9p.Background: Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. Methods: Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. Results: MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). Conclusions: MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.Zainab Samaan, Daria Gaysina, Sarah Cohen-Woods, Nick Craddock, Lisa Jones, Ania Korszun, Mike Owen, Andrew Mente, Peter McGuffin and Anne Farme