Synergistic effects of common schizophrenia risk variants

Schrode, Nadine; Ho, Seok‐Man; Yamamuro, Kazuhiko; Dobbyn, Amanda; Huckins, Laura; Matos, Marliette R.; Cheng, Esther; Deans, P.J. Michael; Flaherty, Erin; Barretto, Natalie; Topol, Aaron; Alganem, Khaled; Abadali, Sonya; Gregory, James A.; Hoelzli, Emily; Phatnani, Hemali; Singh, Vineeta; Girish, Deeptha; Aronow, Bruce J.; McCullumsmith, Robert E.; Hoffman, Gabriel E.; Stahl, Eli A.; Morishita, Hirofumi; Sklar, Pamela; Brennand, Kristen J.

doi:10.1038/s41588-019-0497-5

Cited by 203 publications

(217 citation statements)

References 80 publications

Supporting

Mentioning

198

Contrasting

Order By: Relevance

“…For example, genetic polymorphisms exist in the ACE2 gene [2], which encodes the cellular receptor for SARS-CoV-2; allelic variants of the ACE2 may influence the protein's binding with the virus [3] and subsequent invasion of the cell. In addition, polymorphisms of cellular proteases-believed to facilitate the entry of SARS-CoV-2 into the cell, along with furin [4] and TMPRSS2 [5]-have been shown to exist [6,7]. Indeed, a recent preprint suggests that TMPRSS2 variants and resulting expression may influence COVID-19 severity [8].…”

Section: Genomics Of Susceptibility and Resistancementioning

confidence: 99%

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

et al. 2020

View full text Add to dashboard Cite

The recent coronavirus disease , caused by SARS-CoV-2, is inarguably the most challenging coronavirus outbreak relative to the previous outbreaks involving SARS-CoV and MERS-CoV. With the number of COVID-19 cases now exceeding 2 million worldwide, it is apparent that (i) transmission of SARS-CoV-2 is very high and (ii) there are large variations in disease severity, one component of which may be genetic variability in the response to the virus. Controlling current rates of infection and combating future waves require a better understanding of the routes of exposure to SARS-CoV-2 and the underlying genomic susceptibility to this disease. In this mini-review, we highlight possible genetic determinants of COVID-19 and the contribution of aerosol exposure as a potentially important transmission route of SARS-CoV-2.

show abstract

Section: Genomics Of Susceptibility and Resistancementioning

confidence: 99%

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As combination of ATP6V1A KD and Aβ treatment led to a greater amount of molecular expression change than individual factor perturbation, we explored potential synergistic effects between the two factors 59 . We first modeled the additive effect of differential expression in the individually modulated samples computationally.…”

Section: Neuronal Knockdown Of Vha68-1 a Fly Ortholog Of Atp6v1a Womentioning

confidence: 99%

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H + -ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

show abstract

“…Assays of downstream consequences of variation also confirm biological convergence across association loci. A four-gene-target CRISPRi/a assay revealed that schizophrenia risk genes act synergistically via shared influence on synaptic activity, and concurrent alteration of expression of all four genes results in a cellular transcriptome more accurately reflective of postmortem schizophrenia brain tissue (99). For both rare and common variants, identifying common regulators among risk genes provides information which can refine predictions of disease-related cell types based on their expression of such TFs, RBPs, or epigenomic marks.…”

Section: The Utility Of Mpras For Parsing Linked Variationmentioning

confidence: 99%

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

Mulvey¹,

Lagunas²,

Dougherty³

2020

Preprint

View full text Add to dashboard Cite

Neuropsychiatric phenotypes have been long known to be influenced by heritable risk factors. The past decade of genetic studies have confirmed this directly, revealing specific common and rare genetic variants enriched in disease cohorts. However, the early hope for these studies-that only a small set of genes would be responsible for a given disorder-proved false. The picture that has emerged is far more complex: a given disorder may be influenced by myriad coding and noncoding variants of small effect size, and/or by rare but severe variants of large effect size, many de novo.Noncoding genomic sequences harbor a large portion of these variants, the molecular functions of which cannot usually be inferred from sequence alone. This creates a substantial barrier to understanding the higher-order molecular and biological systems underlying disease risk. Fortunately, a proliferation of genetic technologies-namely, scalable oligonucleotide synthesis, high-throughput RNA sequencing, CRISPR, and CRISPR derivatives-have opened novel avenues to experimentally identify biologically significant variants en masse. These advances have yielded an especially versatile technique adaptable to large-scale functional assays of variation in both untranscribed and untranslated regulatory features: Massively Parallel Reporter Assays (MPRAs). MPRAs are powerful molecular genetic tools that can be used to screen tens of thousands of predefined sequences for functional effects in a single experiment. This approach has several ideal features for psychiatric genetics, but remains underutilized in the field to date. To emphasize the opportunities MPRA holds for dissecting psychiatric polygenicity, we review here its applications in the literature, discuss its ability to test several biological variables implicated in psychiatric disorders, illustrate this flexibility with a proof-of-principle, in vivo cell-type specific implementation of the assay, and envision future outcomes of applying MPRA to both computational and experimental neurogenetics.

show abstract

Synergistic effects of common schizophrenia risk variants

Cited by 203 publications

References 80 publications

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

Contact Info

Product

Resources

About