Risk for nicotine dependence and lung cancer is conferred by mRNA expression levels and amino acid change in CHRNA5.
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.
Wang
Jen C
JC
Department of Psychiatry, Washington University, 660 South Euclid, PO Box 8134, St Louis, MO 63110, USA.
Cruchaga
Carlos
C
Saccone
Nancy L
NL
Bertelsen
Sarah
S
Liu
Pengyuan
P
Budde
John P
JP
Duan
Weimin
W
Fox
Louis
L
Grucza
Richard A
RA
Kern
Jason
J
Mayo
Kevin
K
Reyes
Oliver
O
Rice
John
J
Saccone
Scott F
SF
Spiegel
Noah
N
Steinbach
Joseph H
JH
Stitzel
Jerry A
JA
Anderson
Marshall W
MW
You
Ming
M
Stevens
Victoria L
VL
Bierut
Laura J
LJ
Goate
Alison M
AM
D000483:Alleles; D019943:Amino Acid Substitution; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000378:metabolism
C523021:CHRNA1 protein, human; D012333:RNA, Messenger; D011978:Receptors, Nicotinic