Determining which of the multitude of variants carried by an individual are responsible for a given phenotype represents a massive task, especially if the causal alleles are relatively anonymous in terms of known functional consequences. Because only a small proportion will have obvious functional consequences for the resultant protein, lesser evidence of association may suffice to implicate variants of this sort. The best approaches for combining functional credibility and statistical support in the evaluation of such variants remain to be determined. GWAS have tended to focus almost exclusively on statistical evidence and de-emphasize considerations of biological plausibility, but the challenges of sifting through the millions of rare variants in which two individuals differ may prompt a return to biology if rare variants are to be grouped and analysed properly.
