Six of the top variant sets were located in alcohol or aldehyde dehydrogenase genes. These genes encode for different enzymes that are involved in alcohol metabolism. Some of the strongest and most widely replicated genetic associations for alcohol dependence have occurred with common variants in these genes. There has been limited work to date examining the role of rare variants in these genes in AD. Only one study examined rare variants and found an association with rare variants across the entire ADH gene cluster (Zuo et al., 2013c). Our variant set findings suggest a role for both common and rare variants in these genes. Indeed, a recent commentary has called for the need to examine genetic variation across the entire allelic spectrum to identify risk variants for AD (Edenberg and Foroud, 2014). This strategy has proved successful across a number of other disorders such as, for example, nicotine dependence (Olfson et al., 2016) and schizophrenia (Chang et al., 2016), suggesting that there is the potential for a more general trend of both common and rare variants playing a role in risk.
