Both candidate gene association and targeted sequencing studies serve this purpose. Candidate gene association studies replicated and extended 5 of the 11 GWAS results; i.e., CHRNB3/A6, DBH, BDNF, CHRNA5/A3/B4, and EGLN2/CYP2A6/B6. For the other 29 non-GWS candidate genetic loci, 20 and 7 were selected from within and close to linkage peaks, respectively, the exceptions being NRXN1 and DDC (Table 2), which reminds us of the importance of examining suggestive results in GWAS,92 the other two examples being GRIN2B and NTRK2,87 and biologically plausible genes separately. Although we have localized candidate genes within most of the nominated linkage regions, four linkage peaks, on chromosomes 3q26-q27, 5q11.2-q14, 9p21-p24.1, and 17q24.3-q25.3, are still empty, suggesting there are novel susceptibility genes to be discovered in the future. Overlaps and distinctions from the two unbiased approaches and the significant number of loci reproduced or proposed in candidate gene studies suggest that we have many more study targets with good statistical evidence besides the three most replicable GWAS loci. The fourth “immature” approach is also hypothesis driven and has verified the importance of rare variants in
