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Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels
The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.
Metastable phase-separated droplet generation and long-time DNA enrichment by laser-induced Soret effect
Spatiotemporally controlled laser-induced phase separation (LIPS) offers unique research avenues and has potential for biological and biomedical applications. However, LIPS conditions often have drawbacks for practical use, which limit their applications. For instance, LIPS droplets are unstable and diminish after the laser is terminated. Here, we developed a novel LIPS method using laser-induced Soret effect with a simple setup to solve these problems. We generate liquid-liquid phase-separated (LLPS) droplets using LIPS in an aqueous two-phase system (ATPS) of dextran (DEX) and polyethylene glycol (PEG). When DEX-rich droplets were generated in the DEX/PEG mix on the phase boundary, the droplets showed unprecedently high longevity; the DEX droplets were retained over 48 h. This counterintuitive behaviour suggests that the droplet is in an unknown metastable state. By exploiting the capability of DEX-rich droplets to enrich nucleic acid polymers, we achieved stable DNA enrichment in LIPS DEX droplets with a high enrichment factor of 1400 ± 400. Further, we patterned DNA-carrying DEX-rich droplets into a designed structure to demonstrate the stability and spatiotemporal controllability of DEX-rich droplet formation. This is the first report for LIPS droplet generation in a DEX/PEG system, opening new avenues for biological and medical applications of LIPS.
Excess of rare noncoding variants in several type 2 diabetes candidate genes among Asian Indian families
Type 2 diabetes (T2D) etiology is highly complex due to its multiple roots of origin. Polygenic risk scores (PRS) based on genome-wide association studies (GWAS) can partially explain T2D risk. Asian Indian people have up to six times higher risk of developing T2D than European people, and underlying causes of this disparity are unknown.
Mendelian non-syndromic and syndromic hearing loss genes contribute to presbycusis
Age-related (AR) hearing loss (HL) is the most prevalent sensorineural disorder in older adults. Here we demonstrate that rare-variants in well-established Mendelian HL genes play an important role in ARHL etiology. In all we identified 32 Mendelian HL genes which are associated with ARHL. We performed single and rare-variant aggregate association analyses using exome data obtained from white-Europeans with self-reported hearing phenotypes from the UK Biobank. Our analysis revealed previously unreported associations between ARHL and rare-variants in Mendelian non-syndromic and syndromic HL genes, including MYO15A, and WFS1. Additionally, rare-variant aggregate association analyses identified associations with Mendelian HL genes i.e., ACTG1, GRHL2, KCNQ4, MYO7A, PLS1, TMPRSS3, and TNRC6B. Four novel ARHL genes were also detected: FBXO2 and PALM3, implicated in HL in mice, TWF1, associated with HL in Dalmatian dogs, and TXNDC17. In-silico analyses provided further evidence of inner ear expression of these genes in both murine and human models, supporting their relevance to ARHL. Analysis of variants with minor allele frequency >0.005 revealed additional ARHL associations with known e.g., ILDR1 and novel i.e., ABHD12, COA8, KANSL1, SERAC1, and UBE3B Mendelian non-syndromic and syndromic HL genes as well as ARHL associations with genes that have not been previously reported to be involved in HL e.g., VCL. Rare-variants in Mendelian HL genes typically exhibited higher effect sizes for ARHL compared to those in other associated genes. In conclusion, this study highlights the critical role Mendelian non-syndromic and syndromic HL genes play in the etiology of ARHL.
Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.
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