The LD bin containing rs9298626 also contains rs4952 and rs4953, two low frequency synonymous variants in CHRNB3 that have previously been reported to be associated with reduced risk for nicotine dependence18 and increased risk for bipolar disorder (OR = 1.7, 95%, CI = 1.2–2.4, p = 0.001)24. Interestingly the association of rs4952/rs4953 with cocaine use disorder is in the same direction as the association with bipolar disorder (risk) but in the opposite direction to the association with nicotine dependence (protective) suggesting that CHRNB3 variants have pleiotropic effects on substance use disorders and other psychiatric diseases. Many epidemiological studies have reported the common co-occurrence of bipolar disorder and substance dependence272829. Studies have also implicated shared genes with substance dependence and bipolar disorder2930. It is therefore possible that the high frequency of bipolar disorder and substance dependence comorbidity is in part due to common underlying genetic risk factors such as the risk alleles in the CHRNB3-A6 locus reported here.
