The initial search for attention-deficit hyperactivity disorder (ADHD) genes was hypothesis driven and focused on genes involved in neurotransmission, based on evidence from effective pharmacotherapeutic agents, animal model, and neuroimaging studies. Candidate genes, linkage, and genome-wide analyses studies (GWAS) have identified several gene variants involved in neurotransmission which confer a modest risk for ADHD. It is also possible that few common variants conferring risk for ADHD exist in the European population and that very large samples will be necessary to identify them. Structural variant studies are indicating that ADHD genetic risk is likely to be transmitted largely by rare variants that collectively disrupt a sizable constellation of genes, presumably with related functions. This is supported by animal genetic models which also implicate numerous genes involved in complex interactions between neural pathways. Epigenetic factors, environmental factors, and gene regulatory elements most likely also play a role in ADHD genetics.

This chapter reviews the family studies supporting the role of genetics and recent molecular genetic results. Mapping studies using linkage and association methods have had modest success to date despite difficulties in replication between studies. Linkage studies have shown the best support for chromosomal regions: 6q, 8q, 9p, 13q, 14q, and 22q. Several candidate genes first identified in studies of schizophrenia have shown reproducible association in bipolar disorder. Genome-wide association studies (GWAS) have been successful in identifying a few genes with small effects on risk. The data overall suggest a high level of both genic and allelic heterogeneity, as well as, a complex mode of inheritance. The coming availability of economical whole genome sequencing promises availability of complete genomic information. This, and large samples now being collected, may provide the datasets necessary to unravel the genetic complexities of this illness.

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.