We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.
Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain
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A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function
One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010
Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets
A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies
Immune dysregulation and autoimmunity in bipolar disorder: Synthesis of the evidence and its clinical application
Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture
Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
Defining the role of common variation in the genomic and biological architecture of adult human height
UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age
Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans
Perforin-Positive Dendritic Cells Exhibit an Immuno-regulatory Role in Metabolic Syndrome and Autoimmunity
International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus
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Joint Bayesian inference of risk variants and tissue-specific epigenomic enrichments across multiple complex human diseases
Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution
Integrating Gene Expression with Summary Association Statistics to Identify Genes Associated with 30 Complex Traits
Linkage disequilibrium-dependent architecture of human complex traits shows action of negative selection
Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.
Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility
Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth
QTLbase: an integrative resource for quantitative trait loci across multiple human molecular phenotypes
Genome-wide association analysis of 19,629 individuals identifies variants influencing regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits
DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits
Annotations capturing cell type-specific TF binding explain a large fraction of disease heritability.
Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache.
Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia
Leveraging gene co-expression patterns to infer trait-relevant tissues in genome-wide association studies.
Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration
Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures.
Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders.
Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation
A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome
Genome-wide association study of post-traumatic stress disorder reexperiencing symptoms in >165,000 US veterans.
Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration.
Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits.
Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.
Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of complex traits and disease
Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions
Functional architecture of low-frequency variants highlights strength of negative selection across coding and non-coding annotations
Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability
Genetic analyses of human fetal retinal pigment epithelium gene expression suggest ocular disease mechanisms
Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.
Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson's disease.
Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features.
Integrating RNA-Seq with GWAS reveals novel insights into the molecular mechanism underpinning ketosis in cattle.
A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders.
Leveraging molecular quantitative trait loci to understand the genetic architecture of diseases and complex traits
Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes
Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI
Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants.
Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human.
Comprehensive analyses of 723 transcriptomes enhance genetic and biological interpretations for complex traits in cattle
Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders
Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity
Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans
Genetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent
From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases
Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
Integration of GWAS Summary Statistics and Gene Expression Reveals Target Cell Types Underlying Kidney Function Traits.
A tissue-specific collaborative mixed model for jointly analyzing multiple tissues in transcriptome-wide association studies
Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.
Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia.
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
Integrative analysis of scRNA-seq and GWAS data pinpoints periportal hepatocytes as the relevant liver cell types for blood lipids.
The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study.
Global Analysis of Transcription Start Sites in the New Ovine Reference Genome (Oar rambouillet v1.0 )
Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements.
Predicting regulatory variants using a dense epigenomic mapped CNN model elucidated the molecular basis of trait-tissue associations.
Multiple-Tissue Integrative Transcriptome-Wide Association Studies Discovered New Genes Associated With Amyotrophic Lateral Sclerosis
Gene expression imputation and cell type deconvolution in human brain with spatiotemporal precision and its implications for brain-related disorders
Dosage-sensitive molecular mechanisms are associated with the tissue-specificity of traits and diseases
Maternal antioxidant treatment prevents the adverse effects of prenatal stress on the offspring's brain and behavior
Investigating asthma heterogeneity through shared and distinct genetics: Insights from genome-wide cross-trait analysis.
Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism.
A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density.
Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.
Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.
3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.
Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.
Population-specific causal disease effect sizes in functionally important regions impacted by selection.
GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression.
One size does not fit all. Genomics differentiates among anorexia nervosa, bulimia nervosa, and binge-eating disorder.
Genetic analyses of human fetal retinal pigment epithelium gene expression suggest ocular disease mechanisms
A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.
Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders.
Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder.
Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain.
Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.
Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach.
Leveraging Single-Cell RNA-seq Data to Uncover the Association Between Cell Type and Chronic Liver Diseases.
The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls.
Leveraging expression from multiple tissues using sparse canonical correlation analysis and aggregate tests improves the power of transcriptome-wide association studies.
Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer's disease risk.
System Genetics Including Causal Inference Identify Immune Targets for Coronary Artery Disease and the Lifespan.
Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders?
Brain gene co-expression networks link complement signaling with convergent synaptic pathology in schizophrenia.
Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health.
Genoppi is an open-source software for robust and standardized integration of proteomic and genetic data.
Bipolar disorder is characterized by manic and/or depressive episodes and associated with uncommon shifts in mood, activity levels, and energy. Discover the latest research this illness here.