Nominating novel proteins for anxiety via integrating human brain proteomes and genome-wide association study

Jin, Xing; Dong, Shuangshuang; Yang, Yang; Bao, Guangyu; Ma, Haochuan

doi:10.1016/j.jad.2024.04.097

Cited by 2 publications

(1 citation statement)

References 50 publications

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“…Four of these CpGs also had consistent estimates of the reverse effects of current smoking on DNAm (identified by the column “g1_nominal” in Supplementary Table S4 ): cg25612391 ( SLC25A42 ), cg05424060 ( GNAI1 ), cg10590964 (near KIAA2012 ), and cg05877788 ( TP53I13 ). Furthermore, prior pre-clinical and clinical studies have implicated 14 of the 17 mapped genes, including three with potential bidirectional effects, in behavioral or neurological traits, such as alcohol dependence ( OSBPL5 ) 28 , cocaine use ( SLCO5A1 ) 29 , anxiety ( CCDC92 ) 30 , depression ( GNAI1 ) 31 , encephalomyopathy and brain stress response ( SLC25A42 ) 32 , 33 , and dementia or Alzheimer’s disease pathology ( SIAH3 , SRM , TP53I13 ) 34 – 36 .…”

Section: Resultsmentioning

confidence: 99%

Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation

Singh,

Dolan,

Lapato

et al. 2024

Preprint

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Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking’s causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm’s effects on smoking annotate to genes involved in G protein-coupled receptor signaling (GNG7,RGS3) and innate immune response (SLC15A4), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.

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Section: Resultsmentioning

confidence: 99%

Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation

Singh,

Dolan,

Lapato

et al. 2024

Preprint

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Multi-Omics Integration Analysis Pinpoint Proteins Influencing Brain Structure and Function: Toward Drug Targets and Neuroimaging Biomarkers for Neuropsychiatric Disorders

Wang,

Zhang,

Gong

et al. 2024

IJMS

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Integrating protein quantitative trait loci (pQTL) data and summary statistics from genome-wide association studies (GWAS) of brain image-derived phenotypes (IDPs) can benefit in identifying IDP-related proteins. Here, we developed a systematic omics-integration analytic framework by sequentially using proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization (COLOC) analyses to identify the potentially causal brain and plasma proteins for IDPs, followed by pleiotropy analysis, mediation analysis, and drug exploration analysis to investigate potential mediation pathways of pleiotropic proteins to neuropsychiatric disorders (NDs) as well as candidate drug targets. A total of 201 plasma proteins and 398 brain proteins were significantly associated with IDPs from PWAS analysis. Subsequent MR and COLOC analyses further identified 313 potentially causal IDP-related proteins, which were significantly enriched in neural-related phenotypes, among which 91 were further identified as pleiotropic proteins associated with both IDPs and NDs, including EGFR, TMEM106B, GPT, and HLA-B. Drug prioritization analysis showed that 6.33% of unique pleiotropic proteins had drug targets or interactions with medications for NDs. Nine potential mediation pathways were identified to illustrate the mediating roles of the IDPs in the causal effect of the pleiotropic proteins on NDs, including the indirect effect of TMEM106B on Alzheimer’s disease (AD) risk via radial diffusivity (RD) of the posterior limb of the internal capsule (PLIC), with the mediation proportion being 11.18%, and the indirect effect of EGFR on AD through RD of PLIC, RD of splenium of corpus callosum (SCC), and fractional anisotropy (FA) of SCC, with the mediation proportion being 18.99%, 22.79%, and 19.91%, respectively. These findings provide novel insights into pathogenesis, drug targets, and neuroimaging biomarkers of NDs.

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Nominating novel proteins for anxiety via integrating human brain proteomes and genome-wide association study

Cited by 2 publications

References 50 publications

Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation

Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based Mendelian Randomisation

Multi-Omics Integration Analysis Pinpoint Proteins Influencing Brain Structure and Function: Toward Drug Targets and Neuroimaging Biomarkers for Neuropsychiatric Disorders

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