Multiomic prioritisation of risk genes for anorexia nervosa.
paper
Cited
Public
- Authors
- Adams, Danielle M; Reay, William R; Cairns, Murray J
- Year
- 2023
- Journal
- Psychological medicine
- PMID
- 36803885
- DOI
- 10.1017/S0033291723000235
- PMCID
- PMC10600818
BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes. METHODS: We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes. RESULTS: We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene , for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway (overlapping genes = , , , ) as statistically overrepresented. CONCLUSIONS: We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.
TWAS associations and region plot of the densely associated AN signal on chromosome 3. a: Heatmap of genes with at least one Bonferroni significant eQTL tissue associated with AN. Red indicates positive z scores; blue indicates negative z scores (legend). Columns indicates genes, rows indicate tissue models. * Indicates nominally significant genes, ** indicates Benjamini-Hochberg significant associations, *** indicates Bonferroni significant associations. Grey squares indicate that a significantly cis-heritable model of imputed expression data was unavailable in that tissue. b: Relative AN gene and SNP locations and significance. Points in the top panel indicate SNPs, legend indicates r2, left side y-axis indicates the negative log transformed p value of SNPs, right side y-axis indicates the recombination rate (cM/Mb). The bottom panel indicates the location of genes relative to the top panel SNPs. Plot generated using ZoomLocus (Pruim et al., 2010) with 200 kb flanking size. The SNP with the most significant p value in this region: rs73082362 is highlighted.
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| Name | Type |
|---|---|
| 1000 Genomes European subset local | cohort |
| 1000 genomes panel local | drug |
| 1000 Genomes phase 3 European reference panel local | cohort |
| amygdala | anatomy |
| AN | phenotype |
| AN GWAS local | cohort |
| anorexia nervosa | phenotype |
| AN risk local | phenotype |
| anterior cingulate cortex | anatomy |
| ARIH2 local | gene |
| artery tibial local | anatomy |
| Artery tibial local | anatomy |
| blood cohort local | cohort |
| blood plasma protein local | drug |
| brain | anatomy |
| brain spinal cord cervical c-1 local | anatomy |
| Brain spinal cord cervical c-1 local | anatomy |
| C3orf62 local | gene |
| caudate nucleus | anatomy |
| CCDC71 | gene |
| CDK11B local | gene |
| cerebellar hemisphere | anatomy |
| cerebellum | anatomy |
| chr3:48 918 821:48 967 151 local | variant |
| colon local | anatomy |
| Common Mind Consortium | cohort |
| CommonMind Consortium | cohort |
| common variants | cohort |
| cortex | anatomy |
| CRP | drug |
| Ctbp2 | gene |
| CTNNB1 | gene |
| CTNND1 | gene |
| DALRD3 | gene |
| disorder | phenotype |
| dlPFC | anatomy |
| dorsolateral prefrontal cortex | anatomy |
| European ancestry | cohort |
| fasting insulin level local | phenotype |
| FGF23 local | gene |
| finemapping studies local | drug |
| frontal cortex | anatomy |
| gene | gene |
| GOLIM4 local | gene |
| GPR75-ASB3 local | gene |
| GPX1 local | gene |
| GTEx | cohort |
| GTEx v7 | cohort |
| HapMap3 | cohort |
| HapMap3 local | variant |
| HapMap3 panel local | drug |
| hippocampus | anatomy |
| hypothalamus | anatomy |
| IL-1 | drug |
| IL-6 | drug |
| immune function local | drug |
| immune function | phenotype |
| immune-related genes | gene |
| insulin | drug |
| LINC00324 local | gene |
| METSIM | cohort |
| MGMT local | gene |
| MICB local | gene |
| MST1 | gene |
| MST1R | gene |
| NCKIPSD local | gene |
| NLRP3 | gene |
| non-European samples local | cohort |
| NTR | cohort |
| nucleus accumbens | anatomy |
| NXPE1 local | gene |
| other brain regions | anatomy |
| other psychiatric disorders | phenotype |
| plasma | anatomy |
| presynaptic active zone local | phenotype |
| PRKAR2A | gene |
| PROS1 | gene |
| PsychENCODE | cohort |
| PsychENCODE cortical dataset local | cohort |
| putamen | anatomy |
| rare variant | cohort |
| regulation of immune system process local | phenotype |
| RP13-238F13.5 local | gene |
| RP13-28F13.5 local | gene |
| sex | phenotype |
| spinal cord cervical c-1 local | anatomy |
| structural variant | cohort |
| STX19 local | gene |
| substantia nigra | anatomy |
| SUOX local | gene |
| testis | anatomy |
| testis local | drug |
| TNF | gene |
| total cholesterol | phenotype |
| trait | phenotype |
| trans-ancestry GWAS local | cohort |
| TREX1 local | gene |
| TWAS local | drug |
| UK Biobank | cohort |
| ventral striatum | anatomy |
| WDR6 | gene |
| whole blood | anatomy |
| YFS | cohort |
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External
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| A Genetic Atlas of Relationships Between Circulating Metabolites and Liability to Psychiatric Conditions | Kiltschewskij DJ et al. | β | 2025 | β |
| Causal effects of gut microbiota, metabolites, immune cells, liposomes, and inflammatory proteins on anorexia nervosa: A mediation joint multi-omics Mendelian randomization analysis. | Li Z et al. | β | 2025 | β |
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| Drug repurposing for Alzheimer's disease integrating transcriptome-wide association study and biological network analysis. | Wang X et al. | β | 2025 | β |
| Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. | Strom NI et al. | β | 2025 | β |
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| Utilising genomic association data for causal inference in anorexia nervosa. | Adams DM et al. | β | 2025 | β |
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