As indicated in Table 2, the pathways reaching statistical significance form chains of pathways, rather than being isolated pathways spread across the genome. We identified several biological pathways significantly associated with quantity smoked (see Table 2a). Highly enriched are the neuronal system pathways harbouring the nicotinic acetylcholine receptor genes expressing the α (CHRNA 1-9), β (CHRNB 1-4), γ, δ and ε subunits; the three most strongly associated pathways were the highly calcium permeable postsynaptic nicotinic acetylcholine receptors pathway (P=4.90E-42), the acetylcholine binding and downstream events (P=3.11E-41) and the presynaptic nicotinic acetylcholine receptors (P=8.42E-32) pathway. Note that some of the genes are assigned to more than one pathway, indicating that they play roles in multiple biological processes underlying the smoking behaviours. For instance, the CHRNA3/5 gene cluster on 15q25 (see Supplemental Table S6), was assigned to all three top pathways in the quantity smoked analysis. Excluding this gene cluster from the analysis showed that while the highly calcium permeable postsynaptic nicotinic acetylcholine receptors and the acetylcholine binding and downstream events pathways remained highly significant (i.e., P=1.27E-22 and P= 1.18E-21, respectively), the
