Biology subjects

Kanai, M.

Publications and source records attributed to Kanai, M..

30 records · Page 2Linked to original sources

bioRxiv2021

Analysis of genetic dominance in the UK Biobank

Classical statistical genetic theory defines dominance as a deviation from a purely additive effect. Dominance is well documented in model organisms and plant/animal breeding; outside of rare monogenic traits, however, evidence in humans is limited. We evaluated dominance effects in >1,000 phenotypes in the UK Biobank through GWAS, identifying 175 genome-wide significant loci (P < 4.7 x 10-11). Power to detect non-additive loci is low: we estimate a 20-30 fold increase in sample size is required to detect dominance loci to significance levels observed at additive loci. By deriving a new dominance form of LD-score regression, we found no evidence of a dominance contribution to phenotypic variance tagged by common variation genome-wide (median fraction 5.73 x 10-4). We introduce dominance fine-mapping to explore whether the more rapid decay of dominance linkage disequilibrium can be leveraged to find causal variants. These results provide the most comprehensive assessment of dominance trait variation in humans to date.

genetics↗

bioRxiv2021

Multi-Ancestry Meta-Analysis yields novel genetic discoveries and ancestry-specific associations

We present a new method, Multi-Ancestry Meta-Analysis (MAMA), which combines genome-wide association study (GWAS) summary statistics from multiple populations to produce new summary statistics for each population, identifying novel loci that would not have been discovered in either set of GWAS summary statistics alone. In simulations, MAMA increases power with less bias and generally lower type-1 error rate than other multi-ancestry meta-analysis approaches. We apply MAMA to 23 phenotypes in East-Asian- and European-ancestry populations and find substantial gains in power. In an independent sample, novel genetic discoveries from MAMA replicate strongly.

genomics↗

bioRxiv2021

Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution

3 untranslated region (3UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3UTRs (MPRAu) to sensitively assay 12,173 3UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3UTR function, suggesting that low-complexity sequences predominately explain 3UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an AU-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14, and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.

genetics↗

bioRxiv2020

Leveraging supervised learning for functionally-informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs

The large majority of variants identified by GWAS are non-coding, motivating detailed characterization of the function of non-coding variants. Experimental methods to assess variants effect on gene expressions in native chromatin context via direct perturbation are low-throughput. Existing high-throughput computational predictors thus have lacked large gold standard sets of regulatory variants for training and validation. Here, we leverage a set of 14,807 putative causal eQTLs in humans obtained through statistical fine-mapping, and we use 6,121 features to directly train a predictor of whether a variant modifies nearby gene expression. We call the resulting prediction the expression modifier score (EMS). We validate EMS by comparing its ability to prioritize functional variants with other major scores. We then use EMS as a prior for statistical fine-mapping of eQTLs to identify an additional 20,913 putatively causal eQTLs, and we incorporate EMS into co-localization analysis to identify 310 additional candidate genes across UK Biobank phenotypes.

genomics↗

bioRxiv2020

Tractor: A framework allowing for improved inclusion of admixed individuals in large-scale association studies.

Admixed populations are routinely excluded from medical genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulations and empirical data focused on admixed African-European individuals. Tractor generates ancestryspecific effect size estimates, can boost GWAS power, and improves the resolution of association signals. Using a local ancestry aware regression model, we replicate known hits for blood lipids in admixed populations, discover novel hits missed by standard GWAS procedures, and localize signals closer to putative causal variants.

genomics↗

bioRxiv2020

HCR-FlowFISH: A flexible CRISPR screening method to identify cis-regulatory elements and their target genes

CRISPR screens for cis-regulatory elements (CREs) have shown unprecedented power to endogenously characterize the non-coding genome. To characterize CREs we developed HCR-FlowFISH (Hybridization Chain Reaction Fluorescent In-Situ Hybridization coupled with Flow Cytometry), which directly quantifies native transcripts within their endogenous loci following CRISPR perturbations of regulatory elements, eliminating the need for restrictive phenotypic assays such as growth or transcript-tagging. HCR-FlowFISH accurately quantifies gene expression across a wide range of transcript levels and cell types. We also developed CASA (CRISPR Activity Screen Analysis), a hierarchical Bayesian model to identify and quantify CRE activity. Using >270,000 perturbations, we identified CREs for GATA1, HDAC6, ERP29, LMO2, MEF2C, CD164, NMU, FEN1 and the FADS gene cluster. Our methods detect subtle gene expression changes and identify CREs regulating multiple genes, sometimes at different magnitudes and directions. We demonstrate the power of HCR-FlowFISH to parse genome-wide association signals by nominating causal variants and target genes.

genomics↗

bioRxiv2020

Genetic analyses identify widespread sex-differential participation bias

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of this participation bias is challenging as it requires the genotypes of unseen individuals. However, we demonstrate that it is possible to estimate comparative biases by performing GWAS contrasting one subgroup versus another. For example, we show that sex exhibits autosomal heritability in the presence of sex-differential participation bias. By performing a GWAS of sex in ~3.3 million males and females, we identify over 158 autosomal loci significantly associated with sex and highlight complex traits underpinning differences in study participation between sexes. For example, the body mass index (BMI) increasing allele at the FTO locus was observed at higher frequency in males compared to females (OR 1.02 [1.02-1.03], P=4.4x10-36). Finally, we demonstrate how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

genetics↗

bioRxiv2019

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

Human genetics seeks a way to improve human health on a global scale. Expectations are running high for polygenic risk scores (PRSs) to be translated into clinical practice to predict an inborn susceptibility to health risks. While risk stratification based on PRS is one way to promote population health, a strategy to utilize genetics to prioritize modifiable risk factors and biomarkers driving heath outcome is also warranted. To this end, here we utilized PRSs to comprehensively investigate the association of the genetic susceptibility to complex traits with human lifespan in collaboration with three worldwide biobanks (ntotal = 675,898). First, we conducted genome-wide association studies for 45 quantitative clinical phenotypes, constructed the individual PRSs, and associated them with the age at death of 179,066 participants in BioBank Japan. The PRSs revealed that the genetic susceptibility of high systolic blood pressure (sBP) was strongly associated with a shorter lifespan (hazard ratio [HR] = 1.03, P = 1.4x10-7). Next, we sought to replicate these associations in individuals of European ancestry in UK Biobank (n = 361,194) and FinnGen (n = 135,638). Among the investigated traits, the individuals with higher blood pressure-related PRSs were trans-ethnically associated with a shorter lifespan (HR = 1.03, Pmeta = 3.9x10-13 for sBP) and parental lifespan (HR = 1.06, PUKBB = 2.0x10-86 for sBP). Further, our trans-biobank study identified additional complex traits associated with lifespan (e.g., obesity, height, serum lipids, and platelet counts). Of them, obesity-related traits showed strikingly heterogeneous effects on lifespan between Japanese and European populations (Pheterogeneity = 9.5x10-8 for body mass index). Through trans-ethnic biobank collaboration, we elucidated the novel value of the PRS study in genetics-driven prioritization of risk factors and biomarkers which can be medically intervened to improve population health.

genetics↗

bioRxiv2019

Population-specific causal disease effect sizes in functionally important regions impacted by selection

Many diseases and complex traits exhibit population-specific causal effect sizes with trans-ethnic genetic correlations significantly less than 1, limiting trans-ethnic polygenic risk prediction. We developed a new method, S-LDXR, for stratifying squared trans-ethnic genetic correlation across genomic annotations, and applied S-LDXR to genome-wide association summary statistics for 31 diseases and complex traits in East Asians (EAS) and Europeans (EUR) (average NEAS=90K, NEUR=267K) with an average trans-ethnic genetic correlation of 0.85 (s.e. 0.01). We determined that squared trans-ethnic genetic correlation was 0.82x (s.e. 0.01) smaller than the genome-wide average at SNPs in the top quintile of background selection statistic, implying more population-specific causal effect sizes. Accordingly, causal effect sizes were more population-specific in functionally important regions, including conserved and regulatory regions. In analyses of regions surrounding specifically expressed genes, causal effect sizes were most population-specific for skin and immune genes and least population-specific for brain genes. Our results could potentially be explained by stronger gene-environment interaction at loci impacted by selection, particularly positive selection.

genetics↗

bioRxiv2019

Large scale genome-wide association study in a Japanese population identified 45 novel susceptibility loci for 22 diseases

INTRODUCTORY PARAGRAPHThe overwhelming majority of participants in current genetic studies are of European ancestry1-3, limiting our genetic understanding of complex disease in non-European populations. To address this, we aimed to elucidate polygenic disease biology in the East Asian population by conducting a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 383 independent signals in 331 loci for 30 diseases, among which 45 loci were novel (P < 5 x 10-8). Compared with known variants, novel variants have lower frequency in European populations but comparable frequency in East Asian populations, suggesting the advantage of this study in discovering these novel variants. Three novel signals were in linkage disequilibrium (r2 > 0.6) with missense variants which are monomorphic in European populations (1000 Genomes Project) including rs11235604(p.R220W of ATG16L2, a autophagy-related gene) associated with coronary artery disease. We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, andidentified 378 significant enrichments across nine diseases (FDR < 0.05) (e.g. NF-{kappa}B for immune-related diseases). This large-scale GWAS in a Japanese population provides insights into the etiology of common complex diseases and highlights the importance of performing GWAS in non-European populations.

genetics↗

bioRxiv2018

Hidden ‘risk’ in polygenic scores: clinical use today could exacerbate health disparities

Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others. This disparity is an inescapable consequence of Eurocentric genome-wide association study biases. This highlights that--unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations--clinical uses of PRS today would systematically afford greater improvement to European descent populations. Early diversifying efforts show promise in levelling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, we must prioritize greater diversity in genetic studies and public dissemination of summary statistics to ensure that health disparities are not increased for those already most underserved.

genetics↗

bioRxiv2018

Molecular typing and macrolide resistance analyses of Treponema pallidumin heterosexuals and men who have sex with men communities in Japan, 2017.

In recent years, syphilis notifications have increased dramatically in Japan. We performed molecular typing and analyzed macrolide resistance of Treponema pallidum samples collected from four clinics and a hospital in Tokyo and Osaka prefectures in 2017.\n\nMacrolide resistant strain type 14d/f was found significantly more in heterosexual syphilis cases compared with those strains identified in men who have sex with men (MSM) syphilis cases. The proportion of 14d/f among heterosexuals was 79% (31/39) compared to 37% (7/19) among MSM [OR, 6.6 (95% CI, 1.7 to 26.7); P=0.002]. 83% (50/60) of the strains were identified as macrolide resistant with an A2058G mutation at the 23S rRNA gene. 90% (35/39) of the heterosexual strains were macrolide resistant, relative to 58% (11/19) of MSM strains; the odds of having the resistant mutation was considerably higher in heterosexuals compared with MSM [OR, 6.4 (95% CI, 1.3 to 33.5); P=0.02]. Heterosexual females and males showed similar distributions, and the results remained the same when restricted to men.\n\nThe strain type distribution and frequency of macrolide resistance differed substantially between heterosexual and MSM syphilis samples, suggesting distinct epidemiologic profiles for the two communities and insight into syphilis transmission dynamics in Japan.

epidemiology↗