ORCID Profile
0000-0002-5625-1189
Current Organisations
University of California, San Diego
,
University of Pennsylvania
,
Biogen Inc
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Publisher: Springer Science and Business Media LLC
Date: 23-02-2023
DOI: 10.1038/S41588-023-01300-6
Abstract: Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing s les from 14 brain datasets to create the MetaBrain resource and performed cis - and trans -expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets ( n ≤ 2,759). Many of the 16,169 cortex cis -eQTLs were tissue-dependent when compared with blood cis -eQTLs. We inferred brain cell types for 3,549 cis -eQTLs by interaction analysis. We prioritized 186 cis -eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis -eQTLs with an inferred cell type, such as a neuron-specific cis -eQTL ( CYP24A1 ) for multiple sclerosis. We further describe 737 trans -eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.
Publisher: Cold Spring Harbor Laboratory
Date: 09-05-2021
DOI: 10.1101/2021.05.04.21256398
Abstract: Nearly two hundred common-variant depression risk loci have been identified by genome-wide association studies (GWAS) 1–4 . However, the impact of rare coding variants on depression remains poorly understood. Here, we present the largest to date exome analysis of depression based on 320,356 UK Biobank participants. We show that the burden of rare disruptive coding variants in loss-of-function intolerant genes is significantly associated with depression risk. Among 30 genes with false discovery rate (FDR) .1, SLC2A1 , a blood-brain barrier glucose transporter underlying GLUT1 deficiency syndrome 5–7 , reached exome-wide significance ( P =2.96e-7). Gene-set enrichment supports neuron projection development and muscle activities 2, 3 as implicated in depression. Integrating exomes with polygenic risk revealed additive contributions from common and rare variants to depression risk. The burden of rare disruptive coding variants for depression overlapped with that of developmental disorder, autism and schizophrenia. Our study provides novel insight into the contribution of rare coding variants on depression and genetic relationships across developmental and psychiatric disorders.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 23-02-2022
DOI: 10.1126/SCITRANSLMED.ABJ0264
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 s les passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2022
DOI: 10.1038/S43587-022-00182-3
Abstract: Genetic predisposition has been shown to contribute substantially to the age at which we die. Genome-wide association studies (GWASs) have linked more than 20 loci to phenotypes related to human lifespan 1 . However, little is known about how lifespan is impacted by gene loss of function. Through whole-exome sequencing of 352,338 UK Biobank participants of European ancestry, we assessed the relevance of protein-truncating variant (PTV) gene burden on in idual and parental survival. We identified four exome-wide significant ( P 4.2 × 10 −7 ) human lifespan genes, BRCA1 , BRCA2 , ATM and TET2 . Gene and gene-set, PTV-burden, phenome-wide association studies support known roles of these genes in cancer to impact lifespan at the population level. The TET2 PTV burden was associated with a lifespan through somatic mutation events presumably due to clonal hematopoiesis. The overlap between PTV burden and common variant-based lifespan GWASs was modest, underscoring the value of exome sequencing in well-powered biobank cohorts to complement GWASs for identifying genes underlying complex traits.
Publisher: Wiley
Date: 23-06-2020
DOI: 10.1002/AJMG.A.61641
Abstract: Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 in iduals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.
Publisher: Springer Science and Business Media LLC
Date: 25-05-2023
DOI: 10.1038/S41588-023-01398-8
Abstract: Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population ( n = 485,930). We identify eight genes ( ADGRB2 , KDM5B , GIGYF1 , ANKRD12 , SLC8A1 , RC3H2 , CACNA1A and BCAS3 ) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population.
Location: United States of America
No related grants have been discovered for Ellen Tsai.