16.5: Genome-wide Association Studies (GWAS)

The majority of phenotypic traits are not associated with simple Mendelian inheritance, rather a number of different genetic genes and the combination of alleles determines the genetic aspect of the trait. In addition, there are often non-genetic, developmental and environmental factors involved. Nutrition factors during developing, exposure to toxins or pathogens and other stressors can influence the final phenotype. A classic example of a trait influenced by both genetics and environment is height. It is known as a quantitative trait, characterized by a simple number.^[563] Estimates for the heritability of height differ between populations, ranging from between ~60 to ~80% of the variation attributed to genetic differences and ~20 to ~40% environmental (nutritional) factors. In addition, height (in humans) is a sexually dimorphic trait - on average males are taller than females.

If variation in many genes is involved how do we identify the genes involved in a particular trait?^[564] Begin with a trait that can be accurately measured. Height is more objectively measured than friendliness. Then we need to identify the genetic differences found between different individuals. Typically between 500,000 to 1 million single nucleotide polymorphisms (SNPs) are used. A useful SNP occurs at high frequency (>10 to 30%) in the population. The SNP need not be located within a particular gene; with a high enough density of SNPs, a SNP will be linked to almost every gene. Of course meiotic recombination can influence who is linked to whom.

The different SNPs present in a particular genome are identified based on nucleotide sequence. Samples of a person’s genome are taken, often from white blood cells that have nuclei. Since alleles and SNPs differ in their nucleotide sequences, two perfectly complementary (single-stranded) DNA molecules bind more strongly to one another than two mis-matched molecules. We can use this difference in binding stability to identify which SNP or allele is present at a particular position. Finally, we ask how the presence of particular SNPs/alleles relates to the trait, for example the height of the person or the levels of low (LDL) and high density (HDL) lipoproteins in their blood. Of course you see some of the issues right away. People are different heights at different times of their lives, and different levels of LDL and HDL depending on their diet, and when they last ate. So the trait we are trying to study has to be accurately and reproducibly measurable.

We then ask which markers (SNPs or alleles) are correlated to the trait phenotype under study. In a large enough population we can identify those markers (alleles and SNPs) that are in or near specific genes associated with the phenotype. Correlation however does not prove causation. It may be that the allele/SNP involves a functionally significant allele. To prove that a particular allele plays a role in producing or modifying a trait, further experimental studies are necessary.^[565]

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