Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

Abstract

Anxiety and stress-related disorders (ASRD) are among the most common mental disorders with the majority of patients suffering from additional disorders. Family and twin studies indicate that genetic and environmental factors are underlying their etiology. As ASRD are likely to configure various expressions of abnormalities in the basic stress-response system, we conducted a genome-wide association study including 12,655 cases with various anxiety and stress-related diagnoses and 19,225 controls. Standard association analyses were performed supplemented by a framework of sensitivity analyses. Variants in PDE4B showed consistent association with ASRD across a wide range of our analyses. In mice models, alternations in PDE4B expression were observed in those mice displaying anxious behavior after exposure to chronic stress. We also showed that 28% of the variance in ASRD was accounted for by common variants and that the genetic signature of ASRD overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

Attentional Control Explains Covariation Between Symptoms of Attention‐Deficit/Hyperactivity Disorder and Anxiety During Adolescence

“…This finding corroborates research linking genetic influences on attentional control with anxiety symptoms (Gagne et al., ) and advances attentional control as a putative mechanism in the comorbidity of ADHD and anxiety during the adolescent years, when both types of problems are salient. Our findings also supplement those from other approaches, such as GWAS, which have found relatively little overlap in polygenic risk scores for children's behavioral problems from early/middle childhood to late childhood/adolescence (Meier et al., ). Thus, while each approach has shortcomings, twin study approaches such as ours identify the extent of the genetic overlap across symptom clusters and disorders and provide a foundation of knowledge for further investigation via other approaches (e.g., GWAS, polygenic risk scores).…”

“…For example, serotonin (Lau et al, 2009;Manor et al, 2001) and dopamine (Bellgrove, Hawi, Kirley, Gill, & Robertson, 2005;Rowe et al, 1998) transporter genes have been associated with both ADHD and anxious traits, though this work has not consistently replicated. Genome-wide association studies (GWAS) support polygenic effects on anxiety (Meier et al, 2018), internalizing (Benke et al, 2014), and ADHD symptoms (Demontis et al, 2019), though such work has not yet addressed comorbidity.…”

Variants in regulatory elements ofPDE4Dassociate with Major Mental Illness in the Finnish population

“…P-values ≤ 0.05 for variables and factors are marked in bold. P-values that surpass the Bonferroni multiple test correction for either the number of endophenotypes (14), the number of factors (5) or g-factor (1) tested are in bold and italics.…”

“…Although their involvement in human neuro-pathophysiology is currently unclear, several studies (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) have implicated PDE4s in psychiatric illnesses, particularly PDE4D and PDE4B. In a GWAS study of patient-related treatment response during antipsychotic therapy, three SNPs, in high linkage disequilibrium (LD), from PDE4D were found to significantly associate with mediating the effects of quetiapine (4).…”

“…With chromosomal translocations (9), SNP based haplotypes (10)(11)(12), and genome-wide SNP association (13) being observed in studies of schizophrenia. Moreover, genome-wide association studies (GWAS) have also identified PDE4B in the studies of anxiety (14).…”