TY - JOUR
T1 - Genetic Association and Expression Analyses of the Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) Gene in Alcohol Use Disorder—Relevance for Pain Signaling and Alcohol Use
AU - Lee, Ji Soo
AU - Sorcher, Jill L.
AU - Rosen, Allison D.
AU - Damadzic, Ruslan
AU - Sun, Hui
AU - Schwandt, Melanie
AU - Heilig, Markus
AU - Kelly, John
AU - Mauro, Kelsey L.
AU - Luo, Audrey
AU - Rosoff, Daniel
AU - Muench, Christine
AU - Jung, Jeesun
AU - Kaminsky, Zachary A.
AU - Lohoff, Falk W.
N1 - Funding Information:
This research was supported by the National Institutes of Health (NIH) intramural funding ZIA-AA000242 (Section on Clinical Genomics and Experimental Therapeutics; to FWL), Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). We thank Erick Singley (Office of the Clinical Director, NIAAA) and Monte J. Phillips (Section on Clinical Genomics and Experimental Therapeutics, NIAAA) for technical support.
Funding Information:
This research was supported by the National Institutes of Health (NIH) intramural funding ZIA-AA000242 (Section?on Clinical Genomics and Experimental Therapeutics; to FWL), Division of Intramural Clinical and Biological Research of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). We thank Erick Singley (Office of the Clinical Director, NIAAA) and Monte J. Phillips (Section?on Clinical Genomics and Experimental Therapeutics, NIAAA) for technical support.
Publisher Copyright:
Copyright © 2018 by the Research Society on Alcoholism
PY - 2018/6
Y1 - 2018/6
N2 - Background: The gene encoding phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. Methods: We conducted a case–control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the μ-opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2 g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2-way analysis of variance. Results: In the case–control association study using an NIAAA discovery sample, 8 SNPs in PIP5K1C were significantly associated with AUD in the African ancestry (AA) group (p < 0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N = 3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (p < 0.05) and BLA (p < 0.01). Conclusions: Our discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up-regulation of PIP5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.
AB - Background: The gene encoding phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. Methods: We conducted a case–control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the μ-opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2 g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2-way analysis of variance. Results: In the case–control association study using an NIAAA discovery sample, 8 SNPs in PIP5K1C were significantly associated with AUD in the African ancestry (AA) group (p < 0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N = 3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (p < 0.05) and BLA (p < 0.01). Conclusions: Our discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up-regulation of PIP5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.
KW - Alcohol
KW - Genetics
KW - PIP5K1C
KW - Pain
KW - Translational Research
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U2 - 10.1111/acer.13751
DO - 10.1111/acer.13751
M3 - Article
C2 - 29667742
AN - SCOPUS:85046675076
SN - 0145-6008
VL - 42
SP - 1034
EP - 1043
JO - Alcoholism: Clinical and Experimental Research
JF - Alcoholism: Clinical and Experimental Research
IS - 6
ER -