ABSTRACT Common SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.

Linkage Disequilibrium

Genome-wide Association Study

Genetic Association

Missing heritability problem

SNP

10.1101/2022.01.07.475305

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Citations (16)

LLR: a latent low-rank approach to colocalizing genetic risk variants in multiple GWAS

Bioinformatics (2017)

Jin Liu Xiang Wan Chaolong Wang Chao Yang Xiaowei Zhou

Genome-wide association studies (GWAS), which genotype millions of single nucleotide polymorphisms (SNPs) in thousands of individuals, are widely used to identify the risk SNPs underlying complex human phenotypes (quantitative traits or diseases). Most conventional statistical methods in GWAS only investigate one phenotype at a time. However, an increasing number of reports suggest the ubiquity of pleiotropy, i.e. many complex phenotypes sharing common genetic bases. This motivated us to leverage pleiotropy to develop new statistical approaches to joint analysis of multiple GWAS.In this study, we propose a latent low-rank (LLR) approach to colocalizing genetic risk variants using summary statistics. In the presence of pleiotropy, there exist risk loci that affect multiple phenotypes. To leverage pleiotropy, we introduce a low-rank structure to modulate the probabilities of the latent association statuses between loci and phenotypes. Regarding the computational efficiency of LLR, a novel expectation-maximization-path (EM-path) algorithm has been developed to greatly reduce the computational cost and facilitate model selection and inference. We demonstrate the advantages of LLR over competing approaches through simulation studies and joint analysis of 18 GWAS datasets.The LLR software is available on https://sites.google.com/site/liujin810822.macyang@ust.hk.edu.Supplementary data are available at Bioinformatics online.

Genome-wide Association Study

Pleiotropy

Genetic Association

Leverage (statistics)

10.1093/bioinformatics/btx512

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Citations (9)

Characterization and sources of carbonaceous aerosol in ambient PM1 in Qingdao, a coastal megacity of northern China from 2017 to 2022

Atmospheric Environment (2024)

Jinhua Du Wenxin Tao Jianli Yang Dantong Liu Chaolong Wang

Megacity

10.1016/j.atmosenv.2024.120666

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Citations (1)

Hybrid Sterility in Rice (Oryza sativa L.) Involves the Tetratricopeptide Repeat Domain Containing Protein

Genetics (2016)

Yang Yu Zhigang Zhao Yanrong Shi Hua Tian Linglong Liu

Intersubspecific hybrid sterility is a common form of reproductive isolation in rice (Oryza sativa L.), which significantly hampers the utilization of heterosis between indica and japonica varieties. Here, we elucidated the mechanism of S7, which specially causes Aus-japonica/indica hybrid female sterility, through cytological and genetic analysis, map-based cloning, and transformation experiments. Abnormal positioning of polar nuclei and smaller embryo sac were observed in F1 compared with male and female parents. Female gametes carrying S7(cp) and S7(i) were aborted in S7(ai)/S7(cp) and S7(ai)/S7(i), respectively, whereas they were normal in both N22 and Dular possessing a neutral allele, S7(n) S7 was fine mapped to a 139-kb region in the centromere region on chromosome 7, where the recombination was remarkably suppressed due to aggregation of retrotransposons. Among 16 putative open reading frames (ORFs) localized in the mapping region, ORF3 encoding a tetratricopeptide repeat domain containing protein was highly expressed in the pistil. Transformation experiments demonstrated that ORF3 is the candidate gene: downregulated expression of ORF3 restored spikelet fertility and eliminated absolutely preferential transmission of S7(ai) in heterozygote S7(ai)/S7(cp); sterility occurred in the transformants Cpslo17-S7(ai) Our results may provide implications for overcoming hybrid embryo sac sterility in intersubspecific hybrid rice and utilization of hybrid heterosis for cultivated rice improvement.

Hybrid seed

10.1534/genetics.115.183848

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Citations (63)

A natural gene drive system confers reproductive isolation in rice

Cell (2023)

Chaolong Wang Jian Wang Jiayu Lu Yehui Xiong Zhigang Zhao

Hybrid sterility restricts the utilization of superior heterosis of indica-japonica inter-subspecific hybrids. In this study, we report the identification of RHS12, a major locus controlling male gamete sterility in indica-japonica hybrid rice. We show that RHS12 consists of two genes (iORF3/DUYAO and iORF4/JIEYAO) that confer preferential transmission of the RHS12-i type male gamete into the progeny, thereby forming a natural gene drive. DUYAO encodes a mitochondrion-targeted protein that interacts with OsCOX11 to trigger cytotoxicity and cell death, whereas JIEYAO encodes a protein that reroutes DUYAO to the autophagosome for degradation via direct physical interaction, thereby detoxifying DUYAO. Evolutionary trajectory analysis reveals that this system likely formed de novo in the AA genome Oryza clade and contributed to reproductive isolation (RI) between different lineages of rice. Our combined results provide mechanistic insights into the genetic basis of RI as well as insights for strategic designs of hybrid rice breeding.

Gamete

Reproductive isolation

Oryza

10.1016/j.cell.2023.06.023

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Citations (37)

Prospective Study on Plasma MicroRNA‐4286 and Incident Acute Coronary Syndrome

Journal of the American Heart Association (2021)

Miaoyan Shen Xuedan Xu Xuezhen Liu Qiu-Hong Wang Wending Li

Background Mounting evidence suggests that circulating microRNAs (miRNAs) are critical indicators of cardiovascular disease. However, prospective studies linking circulating miRNAs to incident acute coronary syndrome (ACS) are limited, and the underlying effect of associated miRNA on incident ACS remains unknown. Methods and Results Based on a 2-stage prospective nested case-control design within the Dongfeng-Tongji cohort, we profiled plasma miRNAs from 23 pairs of incident ACS cases and controls by microarray and validated the candidate miRNAs in 572 incident ACS case-control pairs using quantitative real-time polymerase chain reaction. We observed that plasma miR-4286 was associated with higher risk of ACS (adjusted odds ratio according to an interquartile range increase, 1.26 [95% CI, 1.07-1.48]). Further association analysis revealed that triglyceride was positively associated with plasma miR-4286, and an interquartile range increase in triglyceride was associated with an 11.04% (95% CI, 3.77%-18.83%) increase in plasma miR-4286. In addition, the Mendelian randomization analysis suggested a potential causal effect of triglyceride on plasma miR-4286 (β coefficients: 0.27 [95% CI, 0.01-0.53] and 0.27 [95% CI, 0.07-0.47] separately by inverse variance-weighted and Mendelian randomization-pleiotropy residual sum and outlier tests). Moreover, the causal mediation analysis indicated that plasma miR-4286 explained 5.5% (95% CI, 0.7%-17.0%) of the association of triglyceride with incident ACS. Conclusions Higher level of plasma miR-4286 was associated with an increased risk of ACS. The upregulated miR-4286 in plasma can be attributed to higher triglyceride level and may mediate the effect of triglyceride on incident ACS.

Interquartile range

Mendelian Randomization

10.1161/jaha.120.018999

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Citations (11)

Additional file 27 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Figshare (2023)

Stavroula Kanoni Sarah E. Graham Yuxuan Wang Ida Surakka Shweta Ramdas

Additional file 27: Table S17. Sex-stratified effect sizes in UK Biobank considering all individuals or only those not on cholesterol lowering medications.

Sexual dimorphism

Pleiotropy

10.6084/m9.figshare.22601249

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Citations (0)