Genome-wide association study identifies a novel locus for cannabis dependence

被引：30

作者：

Agrawal, A. ^{[1
]}

Chou, Y-L ^{[1
]}

Carey, C. E. ^{[2
]}

Baranger, D. A. A. ^{[2
]}

Zhang, B. ^{[3
]}

Sherva, R. ^{[4
]}

Wetherill, L. ^{[5
]}

Kapoor, M. ^{[6
]}

Wang, J-C ^{[6
]}

Bertelsen, S. ^{[6
]}

Anokhin, A. P. ^{[1
]}

Hesselbrock, V. ^{[7
]}

Kramer, J. ^{[8
]}

Lynskey, M. T. ^{[9
]}

Meyers, J. L. ^{[10
]}

Nurnberger, J. I. ^{[5
,11
,12
]}

Rice, J. P. ^{[1
]}

Tischfield, J. ^{[13
]}

Bierut, L. J. ^{[1
]}

Degenhardt, L. ^{[14
]}

Farrer, L. A. ^{[4
]}

Gelernter, J. ^{[15
,16
]}

Hariri, A. R. ^{[17
]}

Heath, A. C. ^{[1
]}

Kranzler, H. R. ^{[18
]}

Madden, P. A. F. ^{[1
]}

Martin, N. G. ^{[19
]}

Montgomery, G. W. ^{[20
]}

Porjesz, B. ^{[10
]}

Wang, T. ^{[21
]}

Whitfield, J. B. ^{[19
]}

Edenberg, H. J. ^{[5
,22
]}

Foroud, T. ^{[5
]}

Goate, A. M. ^{[6
]}

Bogdan, R. ^{[2
]}

Nelson, E. C. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Psychiat, 660 South Euclid,CB 8134, St Louis, MO 63110 USA

[2] Washington Univ, Dept Psychol & Brain Sci, St Louis, MO USA

[3] Washington Univ, Dept Dev Biol, Sch Med, St Louis, MO USA

[4] Boston Univ, Dept Med Biomed Genet, Sch Med, Boston, MA 02215 USA

[5] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[6] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[7] Univ Connecticut Hlth, Dept Psychiat, Farmington, CT USA

[8] Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA

[9] Kings Coll London, Addict Dept, Inst Psychiat Psychol & Neurosci, London, England

[10] Suny Downstate Med Ctr, Dept Psychiat, Brooklyn, NY 11203 USA

[11] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA

[12] Indiana Univ Sch Med, Stark Neurosci Ctr, Indianapolis, IN 46204 USA

[13] State Univ New Jersey, Dept Genet, New Brunswick, NJ USA

[14] Univ New South Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia

[15] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA

[16] US Dept Vet Affairs, West Haven, CT USA

[17] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA

[18] Univ Penn, Dept Psychiat, Perelman Sch Med, VISN MIRECC 4,Crescenz VAMC, Philadelphia, PA 19104 USA

[19] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[20] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[21] Washington Univ, Dept Genet, Sch Med, St Louis, MO USA

[22] Indiana Univ, Dept Biochem & Mol Biol, Indianapolis, IN 46204 USA

来源：

MOLECULAR PSYCHIATRY | 2018年 / 23卷 / 05期

基金：

美国国家卫生研究院; 英国医学研究理事会; 澳大利亚研究理事会; 美国国家科学基金会;

关键词：

PARTITIONING HERITABILITY; ENDOCANNABINOID SYSTEM; QUANTITATIVE-TRAIT; GENE-EXPRESSION; USE INITIATION; UNITED-STATES; YOUNG-ADULTS; RISK; ANNOTATION; METAANALYSIS;

D O I：

10.1038/mp.2017.200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P = 1.3E - 8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P = 0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P = 2.85E - 7). No genome-wide significant loci emerged for cannabis dependence criterion count (n = 8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P = 0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

引用

页码：1293 / 1302

页数：10

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