One drawback of the GWAS method is its reliance on linkage disequilibrium. This means that this approach is good for identifying variants that are common in the general population (>1%) but misses rare variants with larger effects on risk that have low linkage disequilibrium with common variants detected with standard genotyping chips. As a way to uncover the missing heritability factors that influence the risk for psychiatric diseases, including addiction, next-generation DNA sequencing combined with the results of association and perhaps linkage studies holds the promise of identifying a larger set of susceptibility loci (9, 46). In contrast to GWAS, sequencing of targeted genomic regions identified from GWAS or linkage analysis, or whole-exome or whole-genome sequencing, improves the ability to discover novel causative or highly penetrant mutations for human diseases.
