Sophia J. Docherty

A genome-wide association study identifies multiple loci associated with mathematics ability and disability

Numeracy is as important as literacy and exhibits a similar frequency of disability. Although its etiology is relatively poorly understood, quantitative genetic research has demonstrated mathematical ability to be moderately heritable. In this first genome‐wide association study (GWAS) of mathematical ability and disability, 10 out of 43 single nucleotide polymorphism (SNP) associations nominated from two high‐ vs. low‐ability (n = 600 10‐year‐olds each) scans of pooled DNA were validated (P < 0.05) in an individually genotyped sample of *2356 individuals spanning the entire distribution of mathematical ability, as assessed by teacher reports and online tests. Although the effects are of the modest sizes now expected for complex traits and require further replication, interesting candidate genes are implicated such as NRCAM which encodes a neuronal cell adhesion molecule. When combined into a set, the 10 SNPs account for 2.9% (F = 56.85; df = 1 and 1881; P = 7.277e–14) of the phenotypic variance. The association is linear across the distribution consistent with a quantitative trait locus (QTL) hypothesis; the third of children in our sample who harbour 10 or more of the 20 risk alleles identified are nearly twice as likely (OR = 1.96; df = 1; P = 3.696e–07) to be in the lowest performing 15% of the distribution. Our results correspond with those of quantitative genetic research in indicating that mathematical ability and disability are influenced by many genes generating small effects across the entire spectrum of ability, implying that more highly powered studies will be needed to detect and replicate these QTL associations.

Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies

BackgroundGenetic influences underpinning complex traits are thought to involve multiple quantitative trait loci (QTLs) of small effect size. Detection of such QTL associations requires systematic screening of large numbers of DNA markers within large sample populations. Using pooled DNA on SNP microarrays to screen for allelic frequency differences between groups such as cases and controls (called SNP Microarray and Pooling, or SNP-MaP) has been validated as an efficient solution on both 10 k and 100 k platforms. We demonstrate that this approach can be effectively applied to the truly genomewide Affymetrix GeneChip® Mapping 500 K Array.ResultsIn comparisons between five independent DNA pools (N ~200 per pool) on separate Affymetrix GeneChip® Mapping 500 K Array sets, we show that, for SNPs with minor allele frequencies > 0.05, the reliability of the rank order of estimated allele frequencies, assessed as the average correlation between allele frequency estimates across the DNA pools, was 0.948 (average mean difference across the five pools = 0.069). Similarly, validity of the SNP-MaP approach was demonstrated by a rank-order correlation of 0.937 (average mean difference = 0.095) between the average DNA pool allele frequency estimates and the allele frequencies of an independent (CEPH) sample of 60 unrelated individually genotyped subjects.ConclusionWe conclude that SNP-MaP can be extended for use on the Affymetrix GeneChip® Mapping 500 K Array, providing a cost-effective, reliable and valid initial screen of 500 K SNP microarrays in genomewide association scans.

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve.

A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs

ABSTRACTBackgroundDopamine receptor D4(DRD4) polymorphisms have been associated with a number of psychiatric disorders, but little is known about the mechanism of these associations. DNA methylation is linked to the regulation of gene expression and plays a vital role in normal cellular function, with abnormal DNA methylation patterns implicated in a range of disorders. Recent evidence suggests DNA methylation can be influenced by cis-acting DNA sequence variation, that is, DNA sequence variation located nearby on the same chromosome.MethodsTo investigate the potential influence of cis-acting genetic elements within DRD4, we analysed DRD4 promoter DNA methylation levels in the transformed lymphoblastoid cell-line DNA of 89 individuals (from 30 family-trios). Five SNPs located +/− 10kb of the promoter region were interrogated for associations with DNA methylation levels.ResultsFour significant SNP associations were found with DNA methylation (rs3758653, rs752306, rs11246228 and rs936465). The associations of rs3758653 and rs936465 with DNA methylation were tested and nominally replicated (p-value < 0.05) in post-mortem brain tissue from an independent sample (N = 18). Interestingly, the DNA methylation patterns observed in post-mortem brain tissue were similar to those observed in transformed lymphoblastoid cell line DNA.ConclusionsThe link reported between DNA sequence and DNA methylation offers a possible functional role to seemingly non-functional SNP associations. DRD4 has been implicated in several psychiatric disease phenotypes and our results shed light upon the possible mode of action of SNP associations in this region.

Multiple polymorphisms in genes of the adrenergic stress system confer vulnerability to alcohol abuse

Environmental factors such as stress influence both the predisposition to and development of alcoholism, as well as have significant implications for alcoholism relapse. One predominant biological response to acute stress is the release of norepinephrine, which activates the peripheral stress response and also the hypothalamic–pituitary–adrenal axis. We aimed to examine the role of two genes of the adrenergic system (SLC6A2 and ADRA2A) in alcoholism by genotyping 21 SNPs in 785 adult alcohol‐dependent patients and 1237 controls. Two single nucleotide polymorphisms (SNP) (rs36020 and rs36029) in SLC6A2 were significantly associated with alcoholism [false discovery rate corrected P‐value (FDR) P = 0.007]. Two SNPs in ADRA2A (rs521674 and rs602618) were associated with a positive family history of alcoholism (FDR P ≤ 0.05). A combined SNP‐set analysis was also carried out to determine the risk of harbouring multiple alcohol risk alleles across SLC6A2 and ADRA2A. Logistic regression analysis revealed that an increase in the number of alcohol risk alleles increased the risk for alcoholism (P = 0.000567, odds ratio = 1.75, 95% confidence interval 1.26–2.44). A three‐SNP haplotype consisting of rs187715, rs36020 and rs40147 alleles, AGC, was also found, which was significantly over‐represented in cases compared with controls (61% versus 56%). We therefore demonstrate an association of SLC6A2 and ADRA2A with adult alcoholism. These data confirm the relevance of the adrenergic stress system when considering genetic predisposition to alcohol dependence and suggest that SLC6A2 and ADRA2A should be studied in additional alcohol‐dependent cohorts.

Gene-Environment Interaction in the Etiology of Mathematical Ability Using SNP Sets

Mathematics ability and disability is as heritable as other cognitive abilities and disabilities, however its genetic etiology has received relatively little attention. In our recent genome-wide association study of mathematical ability in 10-year-old children, 10 SNP associations were nominated from scans of pooled DNA and validated in an individually genotyped sample. In this paper, we use a ‘SNP set’ composite of these 10 SNPs to investigate gene-environment (GE) interaction, examining whether the association between the 10-SNP set and mathematical ability differs as a function of ten environmental measures in the home and school in a sample of 1888 children with complete data. We found two significant GE interactions for environmental measures in the home and the school both in the direction of the diathesis-stress type of GE interaction: The 10-SNP set was more strongly associated with mathematical ability in chaotic homes and when parents are negative.

No evidence for association between BMI and 10 candidate genes at ages 4, 7 and 10 in a large UK sample of twins

BackgroundOver the last decade, associations between Body Mass Index (BMI) and a variety of candidate genes have been reported, but samples have almost all been limited to adults. The purpose of the present study was to test the developmental origins of some of these associations in a large longitudinal sample of children.MethodsFor 10 single-nucleotide polymorphisms (SNPs) in candidate genes reported to be associated with BMI in adults, we examined associations with BMI in a sample of 5000 children (2500 twin pairs) with BMI data at 4, 7 and 10 years. Association analyses were performed using the Quantitative Transmission Disequilibrium Test and we corrected for multiple testing using the False Discovery Rate.ResultsDespite having 80% power to detect associations that account for as little as 0.2% of the variance of BMI, none of the 10 SNPs were significantly associated with BMI at any age, although two SNPs showed trends in the expected direction.ConclusionThe lack of association for these ten previously reported associations, despite our large sample size, is typical of associations between candidate genes and complex traits. However, some of the reported SNP associations with BMI might emerge as we continue to follow the sample into adolescence and adulthood. This report highlights the importance of developmentally appropriate candidate genes.

A common variant in myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults.

The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities (Pcomb=7.71 × 10−10, n=699), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.

The XVth World Congress of Psychiatric Genetics, October 7-11, 2007: Rapporteur summaries of oral presentations

The World Congress of Psychiatric Genetics (WCPG) has become an annual event since the early 1990s sponsored by the International Society of Psychiatric Genetics (ISPG). Each year the latest published and unpublished findings are aired for discussion by representatives of the majority of research programs on this topic world‐wide. The 2007 congress was held in New York City and attracted over 1000 researchers. The topics emphasized included results from whole genome association studies, the significance of copy number variation and the important contributions of epigenetic events to psychiatric disorders. There were over 20 oral sessions devoted to these and other topics of interest. Young investigator recipients of travel awards served as rapporteurs to summarize sessions and these summaries follow.

Studying Rare Genetic Syndromes as a Method of Investigating Aetiology of Normal Variation in Educationally Relevant Traits

Studies using genetically sensitive research designs have contributed greatly to our understanding of the aetiology of variation in educationally relevant traits such as IQ, reading, mathematics, spatial ability and, most recently, exam performance (i.e., General Certificate of Secondary Education — GCSE — in the UK (Shakeshaft et al., 2013).