Common variants of<i>NRXN1, LRP1B</i>and<i>RORA</i>are associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

Alliey‐Rodriguez, Ney; Grey, Todd C.; Shafee, Rebecca; Padmanabhan, Jaya; Tandon, Neeraj; Klinger, Madeline; Spring, Jonathan M.; Coppes, Lucas; Reis, Katherine; Keshavan, Matcheri S.; Gage, Diane; McCarroll, Steven A.; Bishop, Jeffrey R.; Hill, S. Kristian; Reilly, James L.; Lencer, Rebekka; Clementz, Brett A.; Buckley, Peter F.; Meda, Shashwath A.; Narayanan, B. V. Sathia; Glahn, David C.; Pearlson, Godfrey D.; Ivleva, Elena I.; Tamminga, Carol A.; Sweeney, John A.; Curtis, David; Keedy, Sarah K.; Badner, Judith A.; Liu, Chunyu; Gershon, Elliot S.

doi:10.1101/175489

Cited by 4 publications

(3 citation statements)

References 71 publications

(70 reference statements)

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“…LRP6 and LRP4 were previously associated with AD and coronary artery disease [ 62 ]. LRP1B was reported associated with AD and schizophrenia [ 63 ].…”

Section: Resultsmentioning

confidence: 99%

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

et al. 2021

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It is important to develop minimally invasive biomarker platforms to help in the identification and monitoring of patients with Alzheimer’s disease (AD). Assisting in the understanding of biochemical mechanisms as well as identifying potential novel biomarkers and therapeutic targets would be an added benefit of such platforms. This study utilizes a simplified and novel serum profiling platform, using mass spectrometry (MS), to help distinguish AD patient groups (mild and moderate) and controls, as well as to aid in understanding of biochemical phenotypes and possible disease development. A comparison of discriminating sera mass peaks between AD patients and control individuals was performed using leave one [serum sample] out cross validation (LOOCV) combined with a novel peak classification valuation (PCV) procedure. LOOCV/PCV was able to distinguish significant sera mass peak differences between a group of mild AD patients and control individuals with a p value of 10−13. This value became non-significant (p = 0.09) when the same sera samples were randomly allocated between the two groups and reanalyzed by LOOCV/PCV. This is indicative of physiological group differences in the original true-pathology binary group comparison. Similarities and differences between AD patients and traumatic brain injury (TBI) patients were also discernable using this novel LOOCV/PCV platform. MS/MS peptide analysis was performed on serum mass peaks comparing mild AD patients with control individuals. Bioinformatics analysis suggested that cell pathways/biochemical phenotypes affected in AD include those involving neuronal cell death, vasculature, neurogenesis, and AD/dementia/amyloidosis. Inflammation, autoimmunity, autophagy, and blood–brain barrier pathways also appear to be relevant to AD. An impaired VWF/ADAMTS13 vasculature axis with connections to F8 (factor VIII) and LRP1 and NOTCH1 was indicated and is proposed to be important in AD development.

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“…LRP6 and LRP4 were previously associated with AD and coronary artery disease [ 62 ]. LRP1B was reported associated with AD and schizophrenia [ 63 ].…”

Section: Resultsmentioning

confidence: 99%

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

et al. 2021

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“…Furthermore, we found three intron-variants in LRP1B (lowest p -value 8.392 × 10 − 10 ) to be significantly associated with the trait FPD. LRP1B was identified in a GWAS where it was found to be associated with increased ventricular volumes in psychosis [ 27 ]. Another promising gene that might influence the propensity to FP is FGF18 .…”

Section: Discussionmentioning

confidence: 99%

Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

et al. 2020

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Background Feather pecking (FP) is damaging behavior in laying hens leading to global economic losses in the layer industry and massive impairments of animal welfare. The objective of the study was to discover genetic variants and affected genes that lead to FP behavior. To achieve that we imputed low-density genotypes from two different populations of layers divergently selected for FP to sequence level by performing whole genome sequencing on founder and half-sib individuals. In order to decipher the genetic structure of FP, genome wide association studies and meta-analyses of two resource populations were carried out by focusing on the traits ‘feather pecks delivered’ (FPD) and the ‘posterior probability of a hen to belong to the extreme feather pecking subgroup’ (pEFP). Results In this meta-analysis, we discovered numerous genes that are affected by polymorphisms significantly associated with the trait FPD. Among them SPATS2L, ZEB2, KCHN8, and MRPL13 which have been previously connected to psychiatric disorders with the latter two being responsive to nicotine treatment. Gene set enrichment analysis revealed that phosphatidylinositol signaling is affected by genes identified in the GWAS and that the Golgi apparatus as well as brain structure may be involved in the development of a FP phenotype. Further, we were able to validate a previously discovered QTL for the trait pEFP on GGA1, which contains variants affecting NIPA1, KIAA1211L, AFF3, and TSGA10. Conclusions We provide evidence for the involvement of numerous genes in the propensity to exhibit FP behavior that could aid in the selection against this unwanted trait. Furthermore, we identified variants that are involved in phosphatidylinositol signaling, Golgi metabolism and cell structure and therefore propose changes in brain structure to be an influential factor in FP, as already described in human neuropsychiatric disorders.

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“…Combining the two results regarding gray and white matter, we explained the opposite phenomenon (larger vs. lower) as increscent gray matter volumes (caudate, thalamus, and putamen) extruded contiguous white matter (superior corona radiata fiber) in patients with the GG/GT genotype. This interpretation is inspired by Alliey-Rodriguez et al (2017).…”

Section: Main Effect Of Rs3813296 On Causality Connectivity In the Frmentioning

confidence: 99%

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

Cai

Huang

et al. 2020

Front. Neurosci.

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Objectives: The frontal-striatum-thalamus pathway is important in the glutamic neural circuit. The hypofunction of GRIN1 and GRIA2 subunits from glutamic receptors has been hypothesized as the primary process in the etiology of schizophrenia. Identified gene polymorphism involved in the pathogenesis of schizophrenia may uncover relevant mechanism pathways. Methods: We selected two loci of rs11146020 and rs3813296 distributed in GRIN1 and GRIA2 genes and tested their main and interaction effects on causality connections and structural characteristics in the frontal-striatum-thalamus pathway in 55 Han Chinese first-episode negative schizophrenia patients.Results: We found that: (1) rs11146020 has a significant main effect on the causality connections between the bilateral dorsolateral prefrontal cortex, and rs3813296 mainly influences those of the descending pathway from the prefrontal cortex to the striatum;(2) interaction effect of rs11146020 and rs3813296 on causality connections are located in the ascending pathway from the pallidum to the dorsolateral prefrontal cortex; and (3) the two loci have effects on the volumes of several regions of this pathway. Conclusion:Our results suggested there is modulation on glutamic frontal-striatumthalamus pathway by rs11146020 and rs3813296 gene polymorphism. Patients with different genotypes have different neuroimaging characteristics, which indirectly reminded clinicians those patients should receive different clinical interventions.

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Common variants ofNRXN1, LRP1BandRORAare associated with increased ventricular volumes in psychosis - GWAS findings from the B-SNIP deep phenotyping study

Cited by 4 publications

References 71 publications

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

Distinguishing Alzheimer’s Disease Patients and Biochemical Phenotype Analysis Using a Novel Serum Profiling Platform: Potential Involvement of the VWF/ADAMTS13 Axis

Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

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