White, DJ; (2006) Evolutionary history of a South American population isolate and the genetic basis of a complex neuropsychiatric trait. Doctoral thesis , UCL (University College London).

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Abstract

Much has been learnt about the genetics of Homo sapiens over the last 130 years including gene structure and number, genome size, and levels of genetic diversity. Many things remain less well understood, however, not least the genetic basis of common, complex traits and disorders. Consideration of functionally important but non-coding regions may improve understanding. I assessed naturally occurring, genetic variation in the promoters of four serotinergic genes and revealed (75%) to be polymorphic, two-thirds of which (50% overall) had functional variant haplotypes. These promoter-based polymorphisms are good functional candidate loci for psychiatric trait mapping studies. The variation within our genomes is organised by historic evolutionary and demographic events. Populations with unique demographic histories may be important in complex trait gene mapping, and the Antioquia isolate (North-West Colombia) is an example of such a population. Using population genetic analyses I have shown high autosomal diversity in Antioquia structure analysis showed relatedness to be strong with Spain and modest with African and Native American populations, likely reflective of its historic admixture. LD was not pronounced in Antioquia, potentially an artefact of marker selection. However, Antioquia may have an important role in admixture mapping. Mapping multifactorial psychiatric traits and disorders is particularly challenging for geneticists. To investigate the genetics of BPI, I performed a family-based association analysis of the SLC6A4 gene in the Antioquia and CVCR populations using 10 SNPs, 3 STRs and 1 VNTR spanning approximately 300kb, including an assessment of LD structure. Moderate over-transmission in BPI cases was observed for a haplotype consisting of the functional VNTR (the LPR) long allele and an adjacent STR (Antioquia TDT %2= 6.00, p=0.014 CVCR HHRR x2=5.012, p=0.025 both TDT %2= 8.00, p=0.005). Characterising genetic variation at the population level is important to improve population-based genetic association studies of complex traits, and the inclusion of regulatory variation is supported.

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