Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in &gt;1.2 million individuals highlight new therapeutic directions

Levey, Daniel F.; Stein, Murray B.; Wendt, Frank R.; Pathak, Gita A.; Zhou, Hang; Aslan, Mihaela; Quaden, Rachel; Harrington, Kelly; Nuñez, Yaira Z.; Overstreet, Cassie; Radhakrishnan, Krishnan; Sanacora, Gerard; McIntosh, Andrew M.; Shi, Jingchunzi; Shringarpure, Suyash; Concato, John; Polimanti, Renato; Gelernter, Joel

doi:10.1038/s41593-021-00860-2

Cited by 256 publications

(299 citation statements)

References 50 publications

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“…However, these disorders rarely occur in isolation, and GWAS of any given outcome will detect genetic loci related to that outcome via correlated traits. This non-specificity is evident in the ubiquitous genetic correlations detected across psychiatric traits [1][2][3][4][5] . Alcohol use disorders (AUDs) are no exception: AUD are moderately heritable (~50%) 6 , with most of the heritability of AUD shared with other externalizing phenotypes [7][8][9] , and a smaller proportion of genetic effects being specific to alcohol use outcomes 7 .…”

Section: Introductionmentioning

confidence: 99%

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Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk

Barr

Mallard

Sanchez‐Roige

et al. 2021

Preprint

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Importance: Characterizing whether genetic variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk, and, potentially, allows us to design more targeted prevention and interventions. Objective: Employ multivariate methods to tease apart variants associated with problematic alcohol use through either general or specific pathways and compare results to standard univariate genetic analysis of problematic alcohol use. Design: We compared results from a univariate genome wide association study (GWAS) of problematic alcohol use to those from a previous multivariate GWAS of externalizing phenotypes. We identified genetic variants associated with problematic alcohol use through a broad liability to externalizing, and those that remain after removing shared variance with externalizing. We compared these results across SNP overlap, bioannotations, genetic correlations, and polygenic scores. Setting: We included GWAS summary statistics from existing GWAS, and two US based hold out samples: The National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Collaborative Study on the Genetics of Alcoholism (COGA). Participants: Publicly available GWAS of externalizing behaviors and participants in Add Health (N=5,107) and COGA (N=7,483), limited to individuals of European ancestries. Exposure(s): N/A Main Outcome(s) and Measure(s): Outcomes included problematic alcohol use (ALCP-O), shared risk for externalizing (EXT), and problematic alcohol use-specific risk (ALCP-S) for the GWASs; a preregistered list of 99 available phenotypes for genetic correlations; and substance use, substance use disorder criteria, and alcohol misuse in the polygenic score analyses. Results: The analysis differentiated SNPs operating through common versus specific risk pathways. While ALCP-O was associated with multiple phenotypes, ALCP-S was predominantly associated with alcohol use and other forms of psychopathology. Polygenic scores for ALCP-O were associated with a variety of other forms of substance use and substance use disorders, polygenic scores for ALCP-S were only associated with alcohol phenotypes. Polygenic scores for both ALCP-S and EXT show differential patterns of associations with alcohol misuse across development. Conclusions and Relevance: Focusing on the differential impacts of shared and specific risk can better characterize pathways of risk for alcohol use disorders. Multivariate methods can be a useful tool for studying many psychiatric conditions. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice for psychiatric outcomes.

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Section: Introductionmentioning

confidence: 99%

“…Genome-wide association studies (GWAS) are rapidly advancing our ability to detect genetic loci associated with psychiatric and substance use disorders [1][2][3][4][5] . However, these disorders rarely occur in isolation, and GWAS of any given outcome will detect genetic loci related to that outcome via correlated traits.…”

Section: Introductionmentioning

confidence: 99%

Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk

Barr

Mallard

Sanchez‐Roige

et al. 2021

Preprint

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“…The strongest GWAS associations, however, have linked NEGR1 with depression [ 17 , 18 ]. The most recent data from depression patients suggest that the functional impact of NEGR1 might involve systemic regulation of homeostasis, as significant upregulation of NEGR1 has been shown in the hypothalamus [ 19 ] and peripheral blood of depression patients [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

et al. 2021

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In the large GWAS studies, NEGR1 gene has been one of the most significant gene loci for body mass phenotype. The purpose of the current study was to clarify the role of NEGR1 in the maintenance of systemic metabolism, including glucose homeostasis, by using both male and female Negr1−/− mice receiving a standard or high fat diet (HFD). We found that 6 weeks of HFD leads to higher levels of blood glucose in Negr1−/− mice. In the glucose tolerance test, HFD induced phenotype difference only in male mice; Negr1−/− male mice displayed altered glucose tolerance, accompanied with upregulation of circulatory branched-chain amino acids (BCAA). The general metabolomic profile indicates that Negr1−/− mice are biased towards glyconeogenesis, fatty acid synthesis, and higher protein catabolism, all of which are amplified by HFD. Negr1 deficiency appears to induce alterations in the efficiency of energy storage; reduced food intake could be an attempt to compensate for the metabolic challenge present in the Negr1−/− males, particularly during the HFD exposure. Our results suggest that the presence of functional Negr1 allows male mice to consume more HFD and prevents the development of glucose intolerance, liver steatosis, and excessive weight gain.

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“… 2 To date, genome‐wide association study (GWAS) has identified hundreds of susceptibility risk loci of MDD. 3 However, studies of common genetic variations have estimated that the single genetic polymorphism (SNP)‐based heritability was only approximately 9–10%, reflecting a serious missing heritability problem.…”

Section: Tablementioning

confidence: 99%

Large‐scale whole‐exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder

et al. 2021

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In the present study, we performed an exome‐wide investigation of the burden of rare disease‐causing variants for major depressive disorder (MDD) using 16,702 samples from UK biobank. Gene‐based association analysis and candidate gene prioritization analysis indicated that FOXH1 have significant association with MDD. In addition, sphingolipid metabolism pathway was found to be less enriched with rare disease‐causing variants in the MDD group, suggesting that this gene set may be involved in the pathophysiology of MDD.

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Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions

Cited by 256 publications

References 50 publications

Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk

Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk

High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

Large‐scale whole‐exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder

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