Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV.
View Article and Find Full Text PDFCancer Epidemiol Biomarkers Prev
March 2024
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues.
View Article and Find Full Text PDFThe BCG (Bacille Calmette-Guérin) vaccine, introduced 100 years ago for tuberculosis prevention, has emerging therapeutic off-target benefits for autoimmunity. In randomized controlled trials, BCG vaccinations were shown to gradually improve two autoimmune conditions, type 1 diabetes (T1D) and multiple sclerosis. Here, we investigate the mechanisms behind the autoimmune benefits and test the hypothesis that this microbe synergy could be due to an impact on the host T cell receptor (TCR) and TCR signal strength.
View Article and Find Full Text PDFObservational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway.
View Article and Find Full Text PDFOne mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear.
View Article and Find Full Text PDFAims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits.
View Article and Find Full Text PDFHematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort.
View Article and Find Full Text PDFGenomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the gene (rs11466334, risk allele frequency (RAF) = 6.
View Article and Find Full Text PDFHodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-Ts when given alone or with nivolumab were safe and could elicit antitumor effects in vivo in patients with relapsed/refractory (r/r) HL.
View Article and Find Full Text PDFBackground: Thousands of genetic variants have been associated with hematological traits, though target genes remain unknown at most loci. Moreover, limited analyses have been conducted in African ancestry and Hispanic/Latino populations; hematological trait associated variants more common in these populations have likely been missed.
Methods: To derive gene expression prediction models, we used ancestry-stratified datasets from the Multi-Ethnic Study of Atherosclerosis (MESA, including = 229 African American and = 381 Hispanic/Latino participants, monocytes) and the Depression Genes and Networks study (DGN, = 922 European ancestry participants, whole blood).
Background: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented.
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