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      Causal relationships between serum albumin, neuroticism and suicidal ideation in depressed patients: A Mendelian randomization study

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          Abstract

          Although serum albumin and neuroticism have revealed a strong association with suicidal ideation in individuals with depression, the causal relationship between them is uncertain. This study analyzed the causal association of serum albumin, neuroticism and suicidal ideation using large-scale GWAS data and Univariable Mendelian Randomization (UVMR) methods. The Multivariable MR (MVMR) analysis was used to explore the causal pathways. UVMR analysis revealed that genetically determined serum albumin is causally associated with neuroticism ( β = −0.006 S.D.; 95 % CI: 0.009, −0.002; p = 0.003) and suicidal ideation ( β = 0.009 S.D.; 95 % CI: 0.001, 0.016; p = 0.037); and that neuroticism mediates 100 % of the causal association between serum albumin and suicidal ideation in individuals with depression. These findings suggest genetic evidence for the causal effect of serum albumin on suicidal ideation in depressed patients and the significant mediation effect of neuroticism on this causal association. This study proves the protective role of serum albumin for neuroticism and the riskiness of personality traits for suicidal ideation in individuals with depression.

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          Most cited references56

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          Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

          Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.
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            Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

            Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the ‘no horizontal pleiotropy’ assumption can cause severe bias in MR. We developed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that MR-PRESSO is best suited when horizontal pleiotropy occurs in <50% of instruments. Next, we applied MR-PRESSO, along with several other MR tests to complex traits and diseases, and found that horizontal pleiotropy: (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from −131% to 201%; (iii) induced false positive causal relationships in up to 10% of relationships; and (iv) can be corrected in some but not all instances.
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              Mendelian Randomization.

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                Author and article information

                Contributors
                Journal
                Heliyon
                Heliyon
                Heliyon
                Elsevier
                2405-8440
                04 May 2024
                15 May 2024
                04 May 2024
                : 10
                : 9
                : e30718
                Affiliations
                [a ]Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, China
                [b ]Medical Psychological Institute of Central South University, Central South University, Changsha, China
                [c ]National Clinical Research Center on Mental Disorders (Xiangya), Changsha, China
                Author notes
                [* ]Corresponding author. Medical Psychological Center, The Second Xiangya Hospital, Central South University, 139 Renmin Rd, Changsha, Hunan, 410011, China. zhangyipsy@ 123456csu.edu.cn
                Article
                S2405-8440(24)06749-5 e30718
                10.1016/j.heliyon.2024.e30718
                11098842
                6cd9cddf-bd95-4263-a355-2459e1d91f76
                © 2024 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 5 March 2023
                : 28 April 2024
                : 2 May 2024
                Categories
                Research Article

                depression,mendelian randomization,neuroticism,serum albumin,suicidal ideation

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