Genome-wide significant loci for addiction and anxiety

Abstract

Background Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. Methods Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. Results Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2–q21.2, LOD = 3.322) and a broad anxiety phenotype (12q24.32–q24.33, LOD = 2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg = 0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1–q33.2, LOD = 3.054) and drug dependence-anxiety (18p11.23–p11.22, LOD = 3.425). Conclusions This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Co‐shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome

“…There is also genetic overlap for T2D, SCZ, and MDD (Kavanagh, Tansey, O'Donovan, & Owen, ; Lin & Shuldiner, ; Figure ). For instance, the 12q24 locus is linked to MDD, bipolar disorder, SCZ (Cassidy et al, ; Christiansen et al, ; Holmans et al, ), and anxiety (Hodgson et al, ), as well as T2D (Mahtani et al, ) and the associated cardiovascular phenotypes of CAD, myocardial infarction, stroke (Erdmann et al, ; Sherva et al, ), dyslipidemia (Aberg et al, ), early microvascular retinopathy (Ikram et al, ) hypertension, obesity, visceral obesity, and BMI joint to C‐reactive protein (Wilson et al, ; Wu et al, ). Thus, at least one or a few genes and/or gene variants across this locus are expected to explain the pleiotropic or comorbid possibly unitarian linkage of the above‐mentioned phenotypes.…”

“…Some loci have shown linkage in different populations to T2D (Mahtani et al, ), MDD, SCZ, bipolar disorder (Cassidy et al, ; Christiansen, Tan, Kruse, McGue, & Christensen, ; Holmans et al, ), anxiety (Hodgson et al, ), cardiovascular phenotypes such as coronary artery disease [CAD], myocardial infarction, stroke (Erdmann et al, ; Sherva et al, ), dyslipidemia (Aberg et al, ), early microvascular retinopathy (Ikram et al, ), hypertension, obesity, visceral obesity, and body mass index (BMI) joint to C‐reactive protein (Wilson et al, ; Wu et al, ). For instance, within the 12q24 locus, we have identified proteasome 26S subunit, non‐ATPase 9 ( PSMD9 ) as a strong T2D risk gene reporting a strongly significant linkage (Gragnoli, ) as well as conferring risk for depression (Gragnoli, ), while independent research groups have reported PSMD9 as one of the top genes contributing to MDD (Wong, Dong, Andreev, Arcos‐Burgos, & Licinio, ; Wong, Dong, Maestre‐Mesa, & Licinio, ) and SCZ (Lee, Kim, & Song, ).…”

Explaining the association between anxiety disorders and alcohol use disorder: A twin study

“…For instance, personality, socioeconomic status, or a general tendency to psychopathology could influence SAD at a young age and later AUD. Shared genetic risk factors for AUD and anxiety disorders have been found in twin (Lahey, Krueger, Rathouz, Waldman, & Zald, 2017;Nelson et al, 2000;Tambs, Harris, & Magnus, 1997) and molecular genetic studies (Cerdá, Sagdeo, Johnson, & Galea, 2010;Hodgson et al, 2016).…”

Complex Comorbidity of Substance Use Disorders with Anxiety Disorders: Diagnosis and Treatment

“…Hodgson et al examined a sample of Mexican-Americans and identiied a region on chromosome 18, possibly responsible for drug dependence and anxiety comorbidity [29].…”