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Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2

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Standard

Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. / Smith, Andrew H; Ovesen, Peter L; Skeldal, Sune; Yeo, Seungeun; Jensen, Kevin P; Olsen, Ditte; Diazgranados, Nancy; Zhao, Hongyu; Farrer, Lindsay A; Goldman, David; Glerup, Simon; Kranzler, Henry R; Nykjaer, Anders; Gelernter, Joel.

In: Alcoholism: Clinical and Experimental Research, Vol. 42, No. 12, 12.2018, p. 2337-2348.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Smith, AH, Ovesen, PL, Skeldal, S, Yeo, S, Jensen, KP, Olsen, D, Diazgranados, N, Zhao, H, Farrer, LA, Goldman, D, Glerup, S, Kranzler, HR, Nykjaer, A & Gelernter, J 2018, 'Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2', Alcoholism: Clinical and Experimental Research, vol. 42, no. 12, pp. 2337-2348. https://doi.org/10.1111/acer.13890

APA

Smith, A. H., Ovesen, P. L., Skeldal, S., Yeo, S., Jensen, K. P., Olsen, D., Diazgranados, N., Zhao, H., Farrer, L. A., Goldman, D., Glerup, S., Kranzler, H. R., Nykjaer, A., & Gelernter, J. (2018). Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcoholism: Clinical and Experimental Research, 42(12), 2337-2348. https://doi.org/10.1111/acer.13890

CBE

Smith AH, Ovesen PL, Skeldal S, Yeo S, Jensen KP, Olsen D, Diazgranados N, Zhao H, Farrer LA, Goldman D, Glerup S, Kranzler HR, Nykjaer A, Gelernter J. 2018. Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcoholism: Clinical and Experimental Research. 42(12):2337-2348. https://doi.org/10.1111/acer.13890

MLA

Smith, Andrew H et al. "Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2". Alcoholism: Clinical and Experimental Research. 2018, 42(12). 2337-2348. https://doi.org/10.1111/acer.13890

Vancouver

Smith AH, Ovesen PL, Skeldal S, Yeo S, Jensen KP, Olsen D et al. Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. Alcoholism: Clinical and Experimental Research. 2018 Dec;42(12):2337-2348. https://doi.org/10.1111/acer.13890

Author

Smith, Andrew H ; Ovesen, Peter L ; Skeldal, Sune ; Yeo, Seungeun ; Jensen, Kevin P ; Olsen, Ditte ; Diazgranados, Nancy ; Zhao, Hongyu ; Farrer, Lindsay A ; Goldman, David ; Glerup, Simon ; Kranzler, Henry R ; Nykjaer, Anders ; Gelernter, Joel. / Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2. In: Alcoholism: Clinical and Experimental Research. 2018 ; Vol. 42, No. 12. pp. 2337-2348.

Bibtex

@article{881559311966448cb600d9c82aaf5e34,
title = "Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2",
abstract = "BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects.RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal.CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.",
author = "Smith, {Andrew H} and Ovesen, {Peter L} and Sune Skeldal and Seungeun Yeo and Jensen, {Kevin P} and Ditte Olsen and Nancy Diazgranados and Hongyu Zhao and Farrer, {Lindsay A} and David Goldman and Simon Glerup and Kranzler, {Henry R} and Anders Nykjaer and Joel Gelernter",
note = "{\textcopyright} 2018 by the Research Society on Alcoholism.",
year = "2018",
month = dec,
doi = "10.1111/acer.13890",
language = "English",
volume = "42",
pages = "2337--2348",
journal = "Alcoholism: Clinical and Experimental Research",
issn = "0145-6008",
publisher = "Wiley-Blackwell Publishing, Inc.",
number = "12",

}

RIS

TY - JOUR

T1 - Risk Locus Identification Ties Alcohol Withdrawal Symptoms to SORCS2

AU - Smith, Andrew H

AU - Ovesen, Peter L

AU - Skeldal, Sune

AU - Yeo, Seungeun

AU - Jensen, Kevin P

AU - Olsen, Ditte

AU - Diazgranados, Nancy

AU - Zhao, Hongyu

AU - Farrer, Lindsay A

AU - Goldman, David

AU - Glerup, Simon

AU - Kranzler, Henry R

AU - Nykjaer, Anders

AU - Gelernter, Joel

N1 - © 2018 by the Research Society on Alcoholism.

PY - 2018/12

Y1 - 2018/12

N2 - BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects.RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal.CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

AB - BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors.METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects.RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal.CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

U2 - 10.1111/acer.13890

DO - 10.1111/acer.13890

M3 - Journal article

C2 - 30252935

VL - 42

SP - 2337

EP - 2348

JO - Alcoholism: Clinical and Experimental Research

JF - Alcoholism: Clinical and Experimental Research

SN - 0145-6008

IS - 12

ER -