A Genome-Wide Association Study Identifies Genetic Variants Associated with Mathematics Ability

Abstract

Mathematics ability is a complex cognitive trait with polygenic heritability. Genome-wide association study (GWAS) has been an effective approach to investigate genetic components underlying mathematic ability. Although previous studies reported several candidate genetic variants, none of them exceeded genome-wide significant threshold in general populations. Herein, we performed GWAS in Chinese elementary school students to identify potential genetic variants associated with mathematics ability. The discovery stage included 494 and 504 individuals from two independent cohorts respectively. The replication stage included another cohort of 599 individuals. In total, 28 of 81 candidate SNPs that met validation criteria were further replicated. Combined meta-analysis of three cohorts identified four SNPs (rs1012694, rs11743006, rs17778739 and rs17777541) of SPOCK1 gene showing association with mathematics ability (minimum p value 5.67 × 10^-10, maximum β -2.43). The SPOCK1 gene is located on chromosome 5q31.2 and encodes a highly conserved glycoprotein testican-1 which was associated with tumor progression and prognosis as well as neurogenesis. This is the first study to report genome-wide significant association of individual SNPs with mathematics ability in general populations. Our preliminary results further supported the role of SPOCK1 during neurodevelopment. The genetic complexities underlying mathematics ability might contribute to explain the basis of human cognition and intelligence at genetic level.

Figure 1. Manhattan plot of –log₁₀ (P values) of meta-analysis result from the additive model after adjustment for sex, age, school and nominal significant principal components in GWAS in Liangshan and Dongming population.

The genome-wide threshold for significant (P = 5 × 10⁻⁸) and suggestive (P = 1 × 10⁻⁵) association are indicated by the horizontal blue and red lines, respectively. 81 SNPs in meta-analysis had P value < 1 × 10⁻⁵, of which 28 met the criteria for further replication. The symbol for the gene where the significant SNPs are in combined meta-analysis is shown in italics.

Figure 2. Signal plot of the discovery-stage GWAS meta-analysis for new math score associated locus.

Signal plot of GWAS meta-analysis results and recombination rates in the GWAS discovery stage. The results (−log₁₀P) are shown for SNPs around the region of SPOCK1 on chromosome 5. The genes within the region of interest are annotated, and the direction of the transcripts is shown by arrows. The key SNP (rs11743006) are shown in purple and the linkage disequilibrium values (r²) for the other SNPs are indicated by the heat scale.