TY - JOUR
T1 - Integrating mRNA and miRNA weighted gene co-expression networks with eQTLs in the nucleus accumbens of subjects with alcohol dependence
AU - Mamdani, Mohammed
AU - Williamson, Vernell
AU - McMichael, Gowon O.
AU - Blevins, Tana
AU - Aliev, Fazil
AU - Adkins, Amy
AU - Hack, Laura
AU - Bigdeli, Tim
AU - Van Der Vaart, Andrew D.
AU - Web, Bradley Todd
AU - Bacanu, Silviu Alin
AU - Kalsi, Gursharan
AU - Kendler, Kenneth S.
AU - Miles, Michael F.
AU - Dick, Danielle
AU - Riley, Brien P.
AU - Dumur, Catherine
AU - Vladimirov, Vladimir I.
AU - Hesselbrock, V.
AU - Edenberg, H. J.
AU - Nurnberger, J.
AU - Foroud, T.
AU - Kuperman, S.
AU - Kramer, J.
AU - Porjesz, B.
AU - Bierut, L.
AU - Goate, A.
AU - Rice, J.
AU - Bucholz, K.
AU - Schuckit, M.
AU - Tischfield, J.
AU - Almasy, L.
AU - Taylor, R.
AU - Dick, D.
AU - Bauer, L.
AU - Koller, D.
AU - O'Connor, S.
AU - Wetherill, L.
AU - Xuei, X.
AU - Chan, Grace
AU - Kang, S.
AU - Manz, N.
AU - Rangaswamy, M.
AU - Rohrbaugh, J.
AU - Wang, J. C.
AU - Brooks, A.
AU - Aliev, F.
AU - Parsian, A.
AU - Reilly, M.
N1 - Funding Information:
Tissues from 41 AD cases and 41 controls were received from the Australian Brain Donor Program, New South Wales Tissue Resource Centre, which is supported by The University of Sydney, National Health and Medical Research Council of Australia, Schizophrenia Research Institute, National Institute of Alcohol Abuse and Alcoholism, and the New South Wales Department of Health ( http://sydney.edu.au/medicine/pathology/trc/ ). Cases were excluded if there was: 1) a history of infectious disease (i.e. HIV/AIDS, hepatitis B or C, or Creutzfeldt-Jakob disease), 2) an unsatisfactory agonal status (determined from the circumstances surrounding the death), 3) a post-mortem interval >48 hours, or 4) significant head injury. In addition to case status, age, sex, ethnicity, brain weight, brain pH, post-mortem interval (PMI), tissue hemisphere, clinical cause of death, blood toxicology at time of death, smoking status, neuropathology, and liver pathology were provided for each subject ().
Funding Information:
We continue to be inspired by our memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, currently a consultant with COGA, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. This national collaborative study is supported by NIH Grant U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). Funding support for GWAS genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institute on Alcohol Abuse and Alcoholism, the NIH GEI (U01HG004438), and the NIH contract "High throughput genotyping for studying the genetic contributions to human disease" (HHSN268200782096C). The authors thank Kim Doheny and Elizabeth Pugh from CIDR and Justin Paschall from the NCBI dbGaP staff for valuable assistance with genotyping and QC in developing the dataset available at dbGaP.
Publisher Copyright:
© 2015 Mamdani et al.
PY - 2015/9/18
Y1 - 2015/9/18
N2 - Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
AB - Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-typespecific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.
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U2 - 10.1371/journal.pone.0137671
DO - 10.1371/journal.pone.0137671
M3 - Article
C2 - 26381263
AN - SCOPUS:84946606555
SN - 1932-6203
VL - 10
JO - PLoS One
JF - PLoS One
IS - 9
M1 - e0137671
ER -