Thread by @Joni_Coleman

I am in the anxiety session at #WCPG2022 First up is @no_strom presenting on the latest @PGCgenetics GWAS. Introduces the phenotype first - clinically distressing fear/worry

Anxiety is under recognised and under treated in primary care - mostly treated by anxiolytics/anti-depressants and psychotherapies. Disorders tend to start in childhood, and are very comorbid with other psych disorders. Multiple risk factors, 30-40% heritability #WCPG2022

Anxiety GWAS has been slower to get going than other disorders - several previous GWAS, up to 5 GWS hits in different GWAS but replication across cohorts needs to be established #WCPG2022

@PGCgenetics GWAS - 36 cohorts, 118k cases, 694k controls. EUR so far, want to expand to other ancestries. MVP and UK Biobank are dominant cohorts #WCPG2022

61 loci associated with anxiety, 11% SNP heritability. This puts ANX in the region of MDD GWAS, maybe with slightly better discovery per case [GWAS more homogeneous than MDD?] #WCPG2022

Effect sizes homogenous across cohorts in most instances. Genetic correlation between cohorts is modest at best #WCPG2022

One factor Genomic SEM is a well fitting model suggesting the anxiety disorders studied are genetically homogeneous #WCPG2022

Expression is brain-enriched [as is the case for all psych disorders]. GABAergic signalling implicated across multiple analyses [driven by GABAR1 association?] #WCPG2022

Genetic correlations across psych disorders, especially MDD and PTSD, as well as neuroticism and depressive symptoms. But not RG=1, so potentially some distinction #WCPG2022

Next up is @ChristelMiddeld discussing a large longitudinal twin study of internalising disorders and comorbidity in childhood and adolescence. #WCPG2022

Data from Netherlands Twin Register, 4.3K MZ (identical) twins, 6.8k DZ (fraternal) twins. Mother and father ratings of ANX, MDD, ODD (oppositional defiant disorder), conduct disorder, ADHD in childhood, converging on a common factor for each disorder #WCPG2022

Modest phenotype correlations across disorders 0.3-0.6, higher between MZ twins than between DZ twins. Correlations are lower in adolescence but still non-zero #WCPG2022

Separate significant A factors for each trait except ADHD. One shared C factor. Separate significant E factor, but shared between some disorders [this was a more complex relationship than I can get across in the tweet] #WCPG2022

Genetic influences correlated across disorders, common environment strongly correlated, non shared environment correlated between ANX and MDD but not with other disorders #WCPG2022

C only important at 7. Genetics explain most of the covariance of ANX with others. Non shared environment correlated of ANX with others increases childhood to adolescence #WCPG2022

[Complex analysis with a lot of information in it - paper needs to be read to fully understand the findings and implications of this work]

Next is @AbiterKuile discussing the relationship between genetic overlap between anxious and fear disorders in @GLADStudy #WCPG2022

Previous (mostly twin) studies have shown that there is a genetic separation between generalised anxiety disorders and the fear disorders #WCPG2022

GLAD has previously shown different definition effects of brief versus detailed phenotyping for GAD compared to fear #WCPG2022

Here, AtK shows a meta-analysis of GLAD, UK Biobank and the Australian Genetics of Depression study. Explored effects of specific versus broad screening #WCPG2022

GAD and fear-based GWAS. GWS associations and gene-based associations. Differ at the significant level (but few hits, so wouldn't expect much covariance) #WCPG2022

Fear and GAD show strong genetic correlation, but was partly driven by results from AGDS. Excluding AGDS, see some distinction between fear and GAD, with stronger GAD-depression correlation, some weaker GAD-physical correlations #WCPG2022

Overall - GAD and fear strongly but not perfectly correlated, and some distinct relationships with other disorders between the different genetic components #WCPG2022

Finally Jack Hettema discusses an MWAS of anxiety. Previous methylation studies have typically been candidate gene approach, some positive results but difficult to gauge robustness. #WCPG2022

MWAS of lifetime anxiety disorders Vs controls in NESDA and replications in Great Smoky Mountains study. Methylation gauged by methyl-CG binding domain sequencing. T cell and B cell MWAS largely unremarkable, monocyte and granulocyte MWAS show some signal. #WCPG2022

One hit in whole blood, but 10s of hits from monocytes (280) and granulocytes (81). Assesses robustness across cohorts - significant overlap of top sites. Enrichment of results in MDD GWAS from Wray et al and in some cell types from PTSD and ANX GWAS #WCPG2022