Self‐reported medication use as an alternate phenotyping method for anxiety and depression in the UK Biobank

The requirement for large sample sizes for psychiatric genetic analyses necessitates novel approaches to derive cases. Anxiety and depression show substantial genetic overlap and share pharmacological treatments. Data on prescribed medication could be effective for inferring case status when other indicators of mental health are unavailable. We investigated self‐reported current medication use in UK Biobank participants of European ancestry. Medication Status cases reported using antidepressant or anxiolytic medication (n = 22,218), controls did not report psychotropic medication use (n = 168,959). A subset, “Medication Only,” additionally did not meet criteria for any other mental health indicator (case n = 2,643, control n = 107,029). We assessed genetic overlap between these phenotypes and two published genetic association studies of anxiety and depression, and an internalizing disorder trait derived from symptom‐based questionnaires in UK Biobank. Genetic correlations between Medication Status and the three anxiety and depression phenotypes were significant (rg = 0.60–0.73). In the Medication Only subset, the genetic correlation with depression was significant (rg = 0.51). The three polygenic scores explained 0.33% – 0.80% of the variance in Medication Status and 0.07% – 0.19% of the variance in Medication Only. This study provides evidence that self‐reported current medication use offers an alternate or supplementary anxiety or depression phenotype in genetic studies where diagnostic information is sparse or unavailable.

[1]  G. Breen,et al.  Multiple measures of depression to enhance validity of major depressive disorder in the UK Biobank , 2020, BJPsych Open.

[2]  G. Breen,et al.  Evaluation of polygenic prediction methodology within a reference-standardized framework , 2020, bioRxiv.

[3]  G. Breen,et al.  Sociodemographic inequalities in lifetime treatment seeking and receipt for common mental health problems , 2020 .

[4]  J. Potash,et al.  Minimal phenotyping yields genome-wide association signals of low specificity for major depression , 2020, Nature Genetics.

[5]  C. Sudlow,et al.  Mental health in UK Biobank – development, implementation and results from an online questionnaire completed by 157 366 participants: a reanalysis , 2020, BJPsych open.

[6]  John P. Rice,et al.  Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank , 2019, Molecular Psychiatry.

[7]  M. Hotopf,et al.  Indicators of mental disorders in UK Biobank—A comparison of approaches , 2019, International journal of methods in psychiatric research.

[8]  G. Breen,et al.  The genetic and environmental hierarchical structure of anxiety and depression in the UK Biobank , 2019, Depression and anxiety.

[9]  P. O’Reilly,et al.  PRSice-2: Polygenic Risk Score software for biobank-scale data , 2019, GigaScience.

[10]  P. Visscher,et al.  Genome-wide association study of medication-use and associated disease in the UK Biobank , 2019, Nature Communications.

[11]  T. Werge,et al.  The Common Genetic Architecture of Anxiety Disorders , 2017, bioRxiv.

[12]  P. Sullivan,et al.  Uncovering the Genetic Architecture of Major Depression , 2019, Neuron.

[13]  J. Deckert,et al.  Genetics of Anxiety Disorders , 2019, Current Psychiatry Reports.

[14]  Blair H. Smith,et al.  Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP , 2019, The Pharmacogenomics Journal.

[15]  R. Marioni,et al.  Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions , 2018, Nature Neuroscience.

[16]  P. Donnelly,et al.  The UK Biobank resource with deep phenotyping and genomic data , 2018, Nature.

[17]  Warren W. Kretzschmar,et al.  Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression , 2017, Nature Genetics.

[18]  S. Lawrie,et al.  Self-reported medication use validated through record linkage to national prescribing data , 2017, Journal of clinical epidemiology.

[19]  E. Banks,et al.  Ascertainment of self-reported prescription medication use compared with pharmaceutical claims data. , 2017, Public health research & practice.

[20]  John P. Rice,et al.  An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype , 2017, Biological Psychiatry.

[21]  C. Sudlow,et al.  Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population , 2017, American journal of epidemiology.

[22]  C. Lewis,et al.  Genetics of Depression: Progress at Last , 2017, Current Psychiatry Reports.

[23]  Ian J. Deary,et al.  Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank , 2017, bioRxiv.

[24]  D. Hinds,et al.  Identification of 15 genetic loci associated with risk of major depression in individuals of European descent , 2016, Nature Genetics.

[25]  H. Möller,et al.  The relevance of ‘mixed anxiety and depression’ as a diagnostic category in clinical practice , 2016, European Archives of Psychiatry and Clinical Neuroscience.

[26]  Warren W. Kretzschmar,et al.  Sparse whole genome sequencing identifies two loci for major depressive disorder , 2015, Nature.

[27]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[28]  田原 康玄,et al.  生活習慣病とgenome-wide association study , 2015 .

[29]  P. Elliott,et al.  UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age , 2015, PLoS medicine.

[30]  H. Zheng,et al.  Performance of Genotype Imputation for Low Frequency and Rare Variants from the 1000 Genomes , 2015, PloS one.

[31]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[32]  Jianxin Shi,et al.  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs , 2013, Nature Genetics.

[33]  P. Visscher,et al.  A Better Coefficient of Determination for Genetic Profile Analysis , 2012, Genetic epidemiology.

[34]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[35]  J. Hettema What is the genetic relationship between anxiety and depression? , 2008, American journal of medical genetics. Part C, Seminars in medical genetics.

[36]  A. Caspi,et al.  Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. , 2007, Archives of general psychiatry.

[37]  D. Watson,et al.  The structure of common DSM-IV and ICD-10 mental disorders in the Australian general population , 2006, Psychological Medicine.

[38]  M C Neale,et al.  A review and meta-analysis of the genetic epidemiology of anxiety disorders. , 2001, The American journal of psychiatry.

[39]  P. Sullivan,et al.  Genetic epidemiology of major depression: review and meta-analysis. , 2000, The American journal of psychiatry.

[40]  K. Kendler,et al.  A twin study of generalized anxiety disorder and major depression , 1995, Psychological Medicine.

[41]  M C Neale,et al.  Major depression and generalized anxiety disorder. Same genes, (partly) different environments? , 1992, Archives of general psychiatry.

[42]  D. Watson,et al.  Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications. , 1991, Journal of abnormal psychology.

[43]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[44]  S. Mineka,et al.  Comorbidity of anxiety and unipolar mood disorders. , 1998, Annual review of psychology.

[45]  R. Marioni,et al.  Edinburgh Research Explorer Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways , 2022 .