All of the major linkage studies relied on the qualitative diagnosis of autism for their analysis. Their results strongly suggest that individual common genetic risk factors are not likely to cause the entire core deficits required for the broad diagnosis of autism or autism spectrum disorders (ASD). Thus, it is necessary to define more precise intermediate phenotypes or endophenotypes that comprise components of the disorder that might be more closely related to a few single genes of small effect size. Endophenotypes are heritable traits characteristic of the disorder and are present in relatives of affected individuals more frequently than in the unrelated general population. The vast majority of association studies have involved the assessment of single candidate genes whose selection was based either on biological hypotheses or on published linkage regions. Similar to other complex genetic diseases, identifying significant genome-wide linkage and association signals in autism has been challenging.

This chapter focuses on alcohol dependence (alcoholism), because the diagnosis is more reliable and because most of the genetic data focus on dependence. The earliest genetic association studies in alcoholism were candidate gene studies targeting coding variations in the genes that metabolize alcohol. Certain variations in alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) genes have very strong effects on the risk for alcoholism. Variations in other genes appear to have a much smaller effect on risk. Linkage studies and their follow-up, along with candidate gene studies and genome-wide association studies (GWAS), are beginning to fill the gaps. Initial findings must be confirmed in independent studies, and much work remains to elucidate the mechanisms involved. The future will involve studies of epigenetic factors, copy number variants, and gene expression, as well as tests for rare variants of large effect in specific families.