Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

Joseph D. Deak; Hang Zhou; Marco Galimberti; Daniel F. Levey; Frank R. Wendt; Sandra Sanchez-Roige; Alexander S. Hatoum; Emma C. Johnson; Yaira Z. Nunez; Ditte Demontis; Anders D. Børglum; Veera M. Rajagopal; Mariela V. Jennings; Rachel L. Kember; Amy C. Justice; Howard J. Edenberg; Arpana Agrawal; Renato Polimanti; Henry R. Kranzler; Joel Gelernter

doi:10.1038/s41380-022-01709-1

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

Joseph D. Deak
, Hang Zhou
, Marco Galimberti
, Daniel F. Levey
, Frank R. Wendt
, Sandra Sanchez-Roige
, Alexander S. Hatoum
, Emma C. Johnson
, Yaira Z. Nunez
, Ditte Demontis
, Anders D. Børglum
, Veera M. Rajagopal
, Mariela V. Jennings
, Rachel L. Kember
, Amy C. Justice
, Howard J. Edenberg
, Arpana Agrawal
, Renato Polimanti
, Henry R. Kranzler
, Joel Gelernter

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

Abstract

Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (N_cases = 20,686;N_effective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h²_SNP) and genetic correlations (r_g). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10⁻⁸) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10⁻¹⁰) and two OPRM1 variants (rs1799971, p = 4.92 × 10⁻⁰⁹; rs79704991, p = 1.11 × 10⁻⁰⁸; r² = 0.02). Rs1799971 (p = 4.91 × 10⁻⁰⁸) and another OPRM1 variant (rs9478500; p = 1.95 × 10⁻⁰⁸; r² = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h²_SNP was 12.75%, with strong r_g with CanUD (r_g = 0.82; p = 1.14 × 10⁻⁴⁷) and AUD (r_g = 0.77; p = 6.36 × 10⁻⁷⁸). The OUD-MTAG resulted in a GWAS N_equivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10⁻¹⁶) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10⁻¹³) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

Original language	English
Pages (from-to)	3970-3979
Number of pages	10
Journal	Molecular Psychiatry
Volume	27
Issue number	10
DOIs	https://doi.org/10.1038/s41380-022-01709-1
State	Published - Oct 2022

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Deak, J. D., Zhou, H., Galimberti, M., Levey, D. F., Wendt, F. R., Sanchez-Roige, S., Hatoum, A. S., Johnson, E. C., Nunez, Y. Z., Demontis, D., Børglum, A. D., Rajagopal, V. M., Jennings, M. V., Kember, R. L., Justice, A. C., Edenberg, H. J., Agrawal, A., Polimanti, R., Kranzler, H. R., & Gelernter, J. (2022). Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci. Molecular Psychiatry, 27(10), 3970-3979. https://doi.org/10.1038/s41380-022-01709-1

@article{0404c061e6a94837981d265ed26826d1,

title = "Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci",

abstract = "Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75\%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81\% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41\% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.",

author = "Deak, \{Joseph D.\} and Hang Zhou and Marco Galimberti and Levey, \{Daniel F.\} and Wendt, \{Frank R.\} and Sandra Sanchez-Roige and Hatoum, \{Alexander S.\} and Johnson, \{Emma C.\} and Nunez, \{Yaira Z.\} and Ditte Demontis and B{\o}rglum, \{Anders D.\} and Rajagopal, \{Veera M.\} and Jennings, \{Mariela V.\} and Kember, \{Rachel L.\} and Justice, \{Amy C.\} and Edenberg, \{Howard J.\} and Arpana Agrawal and Renato Polimanti and Kranzler, \{Henry R.\} and Joel Gelernter",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = oct,

doi = "10.1038/s41380-022-01709-1",

language = "English",

volume = "27",

pages = "3970--3979",

journal = "Molecular Psychiatry",

issn = "1359-4184",

number = "10",

}

Deak, JD, Zhou, H, Galimberti, M, Levey, DF, Wendt, FR, Sanchez-Roige, S, Hatoum, AS , Johnson, EC, Nunez, YZ, Demontis, D, Børglum, AD, Rajagopal, VM, Jennings, MV, Kember, RL, Justice, AC, Edenberg, HJ, Agrawal, A, Polimanti, R, Kranzler, HR & Gelernter, J 2022, 'Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci', Molecular Psychiatry, vol. 27, no. 10, pp. 3970-3979. https://doi.org/10.1038/s41380-022-01709-1

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci. / Deak, Joseph D.; Zhou, Hang; Galimberti, Marco et al.
In: Molecular Psychiatry, Vol. 27, No. 10, 10.2022, p. 3970-3979.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

AU - Deak, Joseph D.

AU - Zhou, Hang

AU - Galimberti, Marco

AU - Levey, Daniel F.

AU - Wendt, Frank R.

AU - Sanchez-Roige, Sandra

AU - Hatoum, Alexander S.

AU - Johnson, Emma C.

AU - Nunez, Yaira Z.

AU - Demontis, Ditte

AU - Børglum, Anders D.

AU - Rajagopal, Veera M.

AU - Jennings, Mariela V.

AU - Kember, Rachel L.

AU - Justice, Amy C.

AU - Edenberg, Howard J.

AU - Agrawal, Arpana

AU - Polimanti, Renato

AU - Kranzler, Henry R.

AU - Gelernter, Joel

PY - 2022/10

Y1 - 2022/10

N2 - Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

AB - Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.

UR - https://www.scopus.com/pages/publications/85136237374

U2 - 10.1038/s41380-022-01709-1

DO - 10.1038/s41380-022-01709-1

M3 - Article

C2 - 35879402

AN - SCOPUS:85136237374

SN - 1359-4184

VL - 27

SP - 3970

EP - 3979

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 10

ER -

Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci

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