A necessary follow-up step is to evaluate if notable candidate genes map to regions nominated by the current GSMA. A strong candidate gene for nicotine dependence, CHRNA4 (20q13.2–q13.3) (30–34), is located in bin 20.3 (20q13.12–q13.32), where genomewide significant linkage was reached in the primary GSMA of MaxCigs24. CHRNA4, which encodes the nicotinic acetylcholine receptor α4 subunit gene, is highly expressed in the central nervous system (CNS) and plays a major role in tolerance, reward, and the modulation of mesolimbic dopamine function, all of which are critical to the development of nicotine dependence (35). Two genes, PLEKHG1 (36) and OPRM1 (37), are located in bin 6.5 (6q23.2–q25.3), which ranks highest and its adjacent bin 6.6 ranks second highest in the GSMA of FTND. The PLEKHG1 gene contains a pleckstrin homology (PH) domain and is expressed in the brain and peripheral nervous system (38). It is possible that variants of these PH-domain-containing proteins have an impact on the cell-signaling pathways that regulate neuronal plasticity, and thus could influence predisposition to ND. The µ-opioid receptor gene OPRM1 has been found to be associated
