One explanation is that instead of following the common-disease common variant hypothesis, which says that the disease causing variants are common in the population of study and have large effect sizes (Visscher et al., 2012), there may be multiple rare causal variants for AD (Edenberg and Foroud, 2014). GWAS studies would have been unable to detect these rare variants because the analysis methods and technology used are designed to target common variants (Wagner, 2013). There is precedent for rare variants contributing to complex diseases ranging from breast cancer (Easton et al., 2007) to neuropsychiatric disorders (Heinzen et al., 2015). In addition, evolutionary theory predicts that disease-causing variants may be rare owing to negative selection and reduced fitness (Eyre-Walker, 2010). Indeed, it has been demonstrated that genes involved in the absorption, distribution, metabolism, and excretion of endogenous compounds, such as alcohol, have higher rates of selection because of the role these genes play in defending against foreign chemical substances (Li et al., 2011).
