Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5

Abstract

Nicotine dependence risk and lung cancer risk are associated with variants in a region of chromosome 15 encompassing genes encoding the nicotinic receptor subunits CHRNA5, CHRNA3 and CHRNB4. To identify potential biological mechanisms that underlie this risk, we tested for cis-acting eQTLs for CHRNA5, CHRNA3 and CHRNB4 in human brain. Using gene expression and disease association studies, we provide evidence that both nicotine-dependence risk and lung cancer risk are influenced by functional variation in CHRNA5. We demonstrated that the risk allele of rs16969968 primarily occurs on the low mRNA expression allele of CHRNA5. The non-risk allele at rs16969968 occurs on both high and low expression alleles tagged by rs588765 within CHRNA5. When the non-risk allele occurs on the background of low mRNA expression of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower compared to those with the higher mRNA expression. Together, these variants identify three levels of risk associated with CHRNA5. We conclude that there are at least two distinct mechanisms conferring risk for nicotine dependence and lung cancer: altered receptor function caused by a D398N amino acid variant in CHRNA5 (rs16969968) and variability in CHRNA5 mRNA expression.

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction

“…The primary psychiatric diagnoses in this sample were schizophrenia or schizoaffective disorder, substance dependence, and anxiety and depressive disorders; all of these conditions are known to be associated with increased rates of smoking (4,30,33). Previous studies suggest that 398Asn itself is not overrepresented in at least two studies of psychiatric populations (36,37). It is also not overrepresented in our sample (psychiatric illness vs. genotype, n = 309; χ 2 = 0.92, P = 0.630).…”

“…The unique finding here is that psychiatric illnesses affect the same circuit independently from and in addition to the α5 genetic effect. 398Asn has repeatedly shown a signal for smoking (5,7,37,(50)(51)(52)(53)(54) but, thus far, not for increased smoking in other psychiatric diagnoses (36,37). Because the sample sizes for psychiatric diagnoses in the present and many of these previous samples are relatively small, these disorders might potentially show a signal with still larger sample sizes.…”

“…Many mental illnesses-similar to smoking-are highly genetic (34,35), suggesting a potentially shared genetic influence. However, as initial data showed that 398Asn itself was not overrepresented in some psychiatric populations (36,37), this raises an intriguing hypothesis that the high risk of smoking in mental illnesses may not necessarily be related to shared genetics, but rather may be a result of converging neural circuits related to smoking.…”

Gene variance in the nicotinic receptor cluster (CHRNA5‐CHRNA3‐CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers

“…The strong correlation between genetic variants in CHRNA5‐CHRNA3‐CHRNB4 , here represented by rs1051730, and CPD suggests that the minor allele (T) could be associated with reduced sensitivity to plasma nicotine levels, leading to increased tobacco consumption 23. Smokers homozygous for the minor allele inhale more often than noncarriers and heterozygous smokers 7.…”

Striatal α5 Nicotinic Receptor Subunit Regulates Dopamine Transmission in Dorsal Striatum

“…Recently, genome-wide association studies have identified that polymorphisms in nAChR genes in gene clusters for other subunits, ␣5/␣3/␤4 and ␣6/␤3, are associated with tobacco addiction (Thorgeirsson et al, 2008;Saccone et al, 2009;Bierut, 2010). Allelic variation and expression levels of ␣5 subunits have been particularly strongly associated, across independent studies Wang et al, 2009;Bierut, 2010). The ␣5 subunits, like ␤3 subunits, are accessory subunits that are known to modify the properties of ␣4-or ␣6-containing nAChRs respectively (Tumkosit et al, 2006;Grady et al, 2010;Kuryatov et al, 2011), but the roles of ␣5-containing (␣5*) or ␤3* nAChRs in normal brain function and in nicotine action in situ are poorly understood.…”