We note the following limitations of the current study. First, the analyses were limited to the main effects of the genetic variants on smoking behaviors. It is possible that the aggregate effect of genetic variants within the significant pathways on smoking behaviors depends on exposure to environmental risk factors. Such gene-environment interaction remains to be studied, but will become feasible in the coming years, as the requisite large samples with raw genotype data and harmonized (across cohorts) measures of environmental exposures become available 61. Second, HYST identified several genes on chromosome 15q25 as significantly associated with quantity smoked. Aside from the known cluster of genes (IREB2-CHRNA3-CHRNA5-CHRNB4-HYKK-PSMA4), we identified a cluster of three genes on the same chromosome 15 (ADAMTS7, MORF4L1 and LOC646938, P=4.48E-17, 1.18E-06 and 1.66E-05, respectively). We note that based on a joint-analysis, SNPs within ADAMTS7 and MORF4L1 were recently listed as candidate signals for smoking behaviour independent of those yielded by the known loci rs16969968 or rs588765 in CHRNA5 31. Further zooming into this genomic region through SNP conditional analysis and molecular experiments is desirable to completely disentangle
