TY - JOUR
T1 - Pleiotropy and genetically inferred causality linking multisite chronic pain to substance use disorders
AU - Koller, Dora
AU - Friligkou, Eleni
AU - Stiltner, Brendan
AU - Pathak, Gita A.
AU - Løkhammer, Solveig
AU - Levey, Daniel F.
AU - Zhou, Hang
AU - Hatoum, Alexander S.
AU - Deak, Joseph D.
AU - Kember, Rachel L.
AU - Treur, Jorien L.
AU - Kranzler, Henry R.
AU - Johnson, Emma C.
AU - Stein, Murray B.
AU - Gelernter, Joel
AU - Polimanti, Renato
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.
PY - 2024/7
Y1 - 2024/7
N2 - Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10−18), CanUD (rg = 0.37, p = 8.21 × 10−37), OUD (rg = 0.20, p = 1.50 × 10−3), and PTU (rg = 0.29, p = 8.53 × 10−12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10−4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10−6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10−8; pain-outcome: beta = 0.09, p = 3.05 × 10−6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10−8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10−5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.
AB - Individuals suffering from chronic pain develop substance use disorders (SUDs) more often than others. Understanding the shared genetic influences underlying the comorbidity between chronic pain and SUDs will lead to a greater understanding of their biology. Genome-wide association statistics were obtained from the UK Biobank for multisite chronic pain (MCP, Neffective = 387,649) and from the Million Veteran Program and the Psychiatric Genomics Consortium meta-analyses for alcohol use disorder (AUD, Neffective = 296,974), cannabis use disorder (CanUD, Neffective = 161,053), opioid use disorder (OUD, Neffective = 57,120), and problematic tobacco use (PTU, Neffective = 270,120). SNP-based heritability was estimated for each of the traits and genetic correlation (rg) analyses were performed to assess MCP-SUD pleiotropy. Bidirectional Mendelian Randomization analyses evaluated possible causal relationships. Finally, to identify and characterize individual loci, we performed a genome-wide pleiotropy analysis and a brain-wide analysis using imaging phenotypes available from the UK Biobank. MCP was positively genetically correlated with AUD (rg = 0.26, p = 7.55 × 10−18), CanUD (rg = 0.37, p = 8.21 × 10−37), OUD (rg = 0.20, p = 1.50 × 10−3), and PTU (rg = 0.29, p = 8.53 × 10−12). Although the MR analyses supported bi-directional relationships, MCP had larger effects on AUD (pain-exposure: beta = 0.18, p = 8.21 × 10−4; pain-outcome: beta = 0.07, p = 0.018), CanUD (pain-exposure: beta = 0.58, p = 2.70 × 10−6; pain-outcome: beta = 0.05, p = 0.014) and PTU (pain-exposure: beta = 0.43, p = 4.16 × 10−8; pain-outcome: beta = 0.09, p = 3.05 × 10−6) than the reverse. The genome-wide analysis identified two SNPs pleiotropic between MCP and all SUD investigated: IHO1 rs7652746 (ppleiotropy = 2.69 × 10−8), and CADM2 rs1248857 (ppleiotropy = 1.98 × 10−5). In the brain-wide analysis, rs7652746 was associated with multiple cerebellum and amygdala imaging phenotypes. When analyzing MCP pleiotropy with each SUD separately, we found 25, 22, and 4 pleiotropic variants for AUD, CanUD, and OUD, respectively. To our knowledge, this is the first large-scale study to provide evidence of potential causal relationships and shared genetic mechanisms underlying MCP-SUD comorbidity.
UR - http://www.scopus.com/inward/record.url?scp=85185132509&partnerID=8YFLogxK
U2 - 10.1038/s41380-024-02446-3
DO - 10.1038/s41380-024-02446-3
M3 - Article
C2 - 38355787
AN - SCOPUS:85185132509
SN - 1359-4184
VL - 29
SP - 2021
EP - 2030
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 7
ER -