A Major Role for Common Genetic Variation in Anxiety Disorders

Purves, Kirstin; Coleman, Jonathan R. I.; Meier, Sandra; Rayner, Christopher; Davis, Katrina; Cheesman, Rosa; Bækvad‐Hansen, Marie; Børglum, Anders D.; Cho, Shing Wan; Deckert, Jürgen; Gaspar, Héléna A.; Bybjerg‐Grauholm, Jonas; Hettema, John M.; Hotopf, Matthew; Hougaard, David M.; Hübel, Christopher; Kan, Carol; McIntosh, Andrew M.; Mors, Ole; Mortensen, Preben Bo; Nordentoft, Merete; Werge, Thomas; Nicodemus, Kristin K.; Mattheisen, Manuel; Breen, Gerome; Eley, Thalia C.

doi:10.1101/203844

Cited by 38 publications

(68 citation statements)

References 69 publications

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“…In this section we compare our GWAS with previous work related to these phenotypes 19,20,30,32 . Using MAGMA 25 , we replicated associations within the CAMKMT gene (P gene =2.97*10 -4 ) identified by the ANGST Consortium 19 , with the lead SNP displaying a different direction of effect (rs1067327, P=1.59*10 -4 , OR=0.93).…”

Section: Our Results In Contextmentioning

confidence: 99%

“…They do however ask for a reflection on the tested hypothesis in the (sensitivity) analyses under consideration. As a final point we would like to stress that our replication efforts were limited by the fact that our study is including a wider range of both ASRD than previous efforts 8,20,30 , which were still restricted in their sample size and power.…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide association studies (GWAS) have proven to be an effective tool for the identification of common genetic variants increasing the susceptibility to complex disorders. Recently, GWAS of ASRD such as panic disorder [5][6][7][8] , post-traumatic stress disorder (PTSD) [9][10][11][12][13][14][15] , generalized anxiety disorders 16 , phobias 17,18 , and a composite indicator of anxiety disorders 19,20 have been published. However, these efforts have been limited by small sample sizes resulting in low overall power to detect significant associations.…”

Section: Introductionmentioning

confidence: 99%

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

Meier

Trontti

Als

et al. 2018

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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.

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Section: Our Results In Contextmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Meier

Trontti

Als

et al. 2018

Preprint

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“…In total, we identified 67 unique genes for the theoretical scores and 64 for the genetic clusters, of which 10 overlapped (Supplementary Tables 14, 15). Compared to previously reported genes for anxiety 271 , depression 40 and neuroticism 272 scales, 20 genes were novel for (and unique to) the genetic clusters, whereas 33 were for the theoretical scores ( Supplementary Fig. 15).…”

Section: Cluster-level Snp-based Heritabilitymentioning

confidence: 57%

Changing perspectives: Towards detailed phenotyping in genetics

Nagel¹

2020

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Mental health problems are highly prevalent in modern-day society. Despite several decades of intensive research aimed at identifying the underlying biological mechanisms, and potential drug targets, pharmacological treatments still have limited success. Since all traits are at least partially influenced by our genetic makeup, using genetic information to increase our understanding of the biological mechanisms underlying mental health problems might eventually benefit patients. Genome-wide association studies (GWAS) provide an exploratory way to identify genetic variants throughout the genome that are, statistically, associated to a trait of interest. The explosion of GWAS studies since 2005 (https://www.ebi.ac.uk/gwas/diagram) has drastically increased our knowledge of the biology of diseases and identified thousands of variants involved in a wide variety of (disease) traits.Yet for many complex traits, like psychiatric disorders, the identified genetic variants explain only a fraction of the variance in the trait. We argue that this may, in part, be the result of the way in which neuropsychiatric traits are operationalized in genetic studies. Typically, participants are classified as cases (i.e., people that suffer from a given psychiatric disorder) or as controls (i.e., not suffering from that particular disorder). However, people suffering from the same disorder may exhibit different sets of symptoms that may, in turn, be influenced by different genetic variants. In other words, the manner in which phenotypes are operationalized will have consequences for the success of genetic analyses. Therefore, in order to properly study the genetic basis of complex behavior, it is vital to think about the exact nature of the phenotypes used in the analysis, and the way they are operationalized. This thesis uses large-scale genetic data and state-of-the-art methods to study the merits of more detailed phenotyping in uncovering the genetics of complex neuropsychiatric traits.

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“…Summary statistics for the exposures were extracted from the largest genome-wide association studies (GWAS) of anxiety (44,465 cases / 58,113 controls) and depression (246,363 cases / 561,190 controls) conducted by the Psychiatric Genomic Consortium (PGC). [28,29] Summary statistics for the outcomes were extracted from the largest GWAS of breast (122,977 cases / 105,974 controls) and endothelia ovarian cancer (25,509 cases / 40,941 controls) conducted by the OncoArray network. [30,31] Materials And Methods…”

Section: Introductionmentioning

confidence: 99%

Do Psychiatric Disorders Influence the Risk of Female Cancer? Results From a Genetic Study

Zhu

Zhang

Niu

et al. 2020

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Background: Depression and anxiety contribute to an increased global burden of disease and affect women more often than men. Despite evidence from experimental data showing a shared biological mechanism involved in both mental health disorders and female hormone-dependent cancers, results from epidemiological investigations remain inconsistent.Methods: We aim to understand a putative causal relationship between psychological distress and female malignancy by conducting a two-sample Mendelian randomization (MR) analysis. We used summary statistics from the hitherto largest genome-wide association studies (GWAS) performed in depression (Ncase=246,363), anxiety (Ncase=44,465), breast (Ncase=122,977) and ovarian (Ncase=25,509) cancer. We constructed strong instruments using the 102 depression-associated SNPs, the 6 anxiety-associated SNPs, and applied several MR approaches.Results: We found that genetic predisposition to depression significantly increased the risk of both overall breast cancer (OR [95%CI] = 1.10 [1.03-1.18]) and its estrogen receptor (ER)- subtype (1.12 [1.01-1.24]), while a borderline significance was observed for ER+ subtype (1.08 [0.99-1.18]). These findings were corroborated by our genetic correlation analysis where a significantly shared genetic basis was observed for depression and breast cancer. On the contrary, we did not identify any causal association of anxiety with breast cancer. None of the mental health traits were associated with the onset of ovarian cancer or its serous subtype. Sensitivity analyses using different sets of instruments revealed consistent results.Conclusions: Our findings suggest that poor mental health condition such as major depression disorder is likely to be causally associated with the development of breast cancer, providing evidence supporting for the potential deleterious consequence of mental illness on cancer onset.

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A Major Role for Common Genetic Variation in Anxiety Disorders

Cited by 38 publications

References 69 publications

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

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

Changing perspectives: Towards detailed phenotyping in genetics

Do Psychiatric Disorders Influence the Risk of Female Cancer? Results From a Genetic Study

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