SUMMARY

Genetic mechanisms of intelligence

The past 150 years have seen major efforts in understanding individual differences in intelligence. This field of research started with Sir Francis Galton’s observation in the second half of the 19th century that family members tend to be more alike than unrelated individuals on intellectual capabilities. Twin studies in the second half of the 20th century showed that familial resemblance in intelligence and differences between unrelated individuals are mainly due to heritable factors. Whole genome linkage studies at the start of the 21st century suggested that some of these heritable factors reside on chromosomes 2 and 6. Candidate gene studies have further yielded a handful of putative genes for intelligence.

The studies included in this thesis aimed to add to the understanding of the genetic variation underlying intelligence. To this end, I adopted several approaches. In chapter 2, I followed up on previous linkage results and carried out an in-silico candidate loci study. From all nominally significant SNPs (39) in the discovery cohort in this study only 5 in 2 genes (ATXN1 and TRIM31) were significantly associated with intelligence in the replication samples (explaining each < 3% of the variance). In chapter 3, I moved from association to causation. In this study, I used a pathway based approach in combination with brain expression information and investigated the role of genetic variants involved in the fatty acid pathway in intelligence. Besides the reported importance of the fatty acid on brain development and cognition, there is no reported empirical observation that fatty acid pathway genetic variants are causative polymorphisms involved on cognitive variance. I found strong evidence that genetic variants inside the FADS1 and FADS2 genes are correlated with brain expression of FADS1 and that most probably this expression is affected by a combined effect of multiple genetic variants. Our findings suggest that genetic variance in the FADS cluster region in combination with food/breast milk intake might alter the composition of the fatty acids in the brain, thereby possibly affecting cognitive behavior.

In Chapter 4, I put the generalist gene hypothesis to a test and found that the SNAP25 gene, which was previously associated with intelligence in the normal range, was also associated with the more extreme form of mental retardation. Our findings suggest that genes involved in synaptic signaling pathways and axonal growth, such as SNAP25, may play a general role on both intellectual ability and disability. In chapter 5, I applied a genome wide association (GWA) analysis strategy in combination with a gene-based approach to find genes involved in educational attainment, which is highly correlated with IQ. In that study we report two novel genes related to educational attainment (AQP4 and GPX2) and confirm the evidence of association of DYNLL2 that was among the top hits in a previous GWA study for educational attainment. In addition I showed that genetic variance in ALDH5A1 and DRD2, previously reported to influence intelligence, also contributed to the genetic variance for educational attainment.

The general conclusions is that my research confirms previous findings, such as: 1-Intelligence is highly heritable. 2- Intelligence is influenced by multiple genetic variants present in different chromosomes. 3- Genetic variants have an additive effect on intelligence. In addition my work revealed new genes and biologic mechanisms involved in intelligence and that these genes influence each other. Future studies should focus on the functional aspects of the genetic variants such as fatty acid metabolism, cell function and gene expression.