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A rare variant in COL11A1 is strongly associated with adult height in Chinese Han population

Journal of Genetics and Genomics 2016年第9期43卷 549-554页

作者： Changbing Shen Xiaodong Zheng Jing Gao Caihong Zhu Randy Ko Xianfa Tang Chao Yang Jinfa Dou Yan Lin Yuyan Cheng Lu Liu Shuangjun Xu Gang Chen Xianbo Zuo Xianyong Yin Liangdan Sun Yong Cui Sen Yang Xuejun Zhang Fusheng Zhou Institute and Department of Dermatology The First Affiliated Hospital Anhui Medical University The Key Laboratory of Dermatology Ministry of Education Anhui Medical University Collaborative Innovation Center for Complex and Severe Dermatosis Anhui Medical University Department of Dermatology The Second Affiliated Hospital Anhui Medical University Department of Biochemistry University of New Mexico Department of Genetics Renaissance Computing Institute University of North Carolina at Chapel Hill Department of Dermatology China-Japan Friendship Hospital

Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies （GWASs） have identified that COL11A1 is an important susceptibility gene for hu- man height. To determine whether the variants of COL11A 1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chrl 103380393 with P value of 4.8 × 10-7. Chrl_103380393 also showed nominal significance in the validation stage （P = 1.21×10 6）. Combined analysis of 16,738 samples strengthened the original association of chrl 103380393 with adult height （Pcombinea - 3.1×10 8）, with an increased height of 0.292sd （standard deviation） per G allele （95% CI： 0.19-0.40）. There was no evidence （P = 0.843） showing that chrl 103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.

关键词： rare variant COL11A1 Adult height Chinese Han population

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Effect of Genome-Wide Genotyping and Reference Panels on rare variants Imputation

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Journal of Genetics and Genomics 2012年第10期39卷 545-550页

作者： Hou-Feng Zheng Martin Ladouceur Celia M.T. Greenwood J. Brent Richards Department of Medicine Human Genetics McGill University Montreal Quebec H3T 1E2 Canada Department of Epidemiology and Biostatistics Lady Davis Institute for Medical Research Jewish General Hospital Montreal Quebec H3T 1E2 Canada Research Center of Montreal Heart Institute Montreal Quebec HIT 1C8 Canada Department of Oncology McGill University Montreal Quebec H3T IE2 Canada Twin Research and Genetic Epidemiology King's College London London SE1 7EH United Kingdom

Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genome-wide genotypic arrays offers a cost-efficient strategy to achieve necessary sample sizes required for adequate statistical power. To estimate the performance of imputation of rare variants, we imputed 153 individuals, each of whom was genotyped on 3 different genotype arrays including 317k, 610k and 1 million single nucleotide polymorphisms （SNPs）, to two different reference panels： HapMap2 and 1000 Genomes pilot March 2010 release （1KGpilot） by using IMPUTE version 2. We found that more than 94% and 84% of all SNPs yield acceptable accuracy （info 〉 0.4） in HapMap2 and 1KGpilot-based imputation, respectively. For rare variants （minor allele frequency （MAF）〈5%）, the proportion of well- imputed SNPs increased as the MAF increased from 0.3% to 5% across all 3 genome-wide association study （GWAS） datasets. The proportion of well-imputed SNPs was 69%, 60% and 49% for SNPs with a MAF from 0.3% to 5% for 1M, 610k and 317k, respectively. None of the very rare variants （MAF 〈 0.3%） were well imputed. We conclude that the imputation accuracy of rare variants increases with higher density of genome-wide genotyping arrays when the size of the reference panel is small. variants with lower MAF are more difficult to impute. These findings have important implications in the design and replication of large-scale sequencing studies.

关键词： Genotype imputation Genome-wide association study 1000 Genome Project HapMap rare variant Common disease

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rare SNP Identified a TCP Transcription Factor Essential for Tendril Development in Cucumber

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Molecular Plant 2015年第12期8卷 1795-1808页

作者： Shenhao Wang Xueyong Yang Mengnan Xu Xingzhong Lin Tao Lin Jianjian Qi Guangjin Shao Nana Tian QingYang Zhonghua Zhang Sanwen Huang Key Laboratory of Biology and Genetic Improvement of Horticultural Crops of Ministry of Agriculture Sino-Dutch Joint Lab of Horticultural Genomics Institute of Vegetables and Flowers Chinese Academy of Agricultural Sciences Beijing 100081 China Agricultural Genome Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 China College of Life Sciences Nanjing Agricultural University Nanjing 210095 China Inner Mongolia Potato Engineering and Technology Research Centre Inner Mongolia University Hohhot 010021 China These authors contributed equally to this article.

rare genetic variants are abundant in genomes but less tractable in genome-wide association study. Here we exploit a strategy of rare variation mapping to discover a gene essential for tendril development in cucumber （Cucumis sativus L.）. In a collection of 〉3000 lines, we discovered a unique tendril-less line that forms branches instead of tendrils and, therefore, loses its climbing ability. We hypothesized that this unusual phenotype was caused by a rare variation and subsequently identified the causative single nucleotide poly- morphism. The affected gene TEN encodes a TCP transcription factor conserved within the cucurbits and is expressed specifically in tendrils, representing a new organ identity gene. The variation occurs within a pro- tein motif unique to the cucurbits and impairs its function as a transcriptional activator. Analyses of transcrip- tomes from near-isogenic lines identified downstream genes required for the tendril＇s capability to sense and climb a support. This study provides an example to explore rare functional variants in plant genomes.

关键词： rare variant TCP transcription factor cucumber tendril homologous organs

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TREM in Alzheimer's Disease: Genetics, Mechanisms and Therapy

TREM in Alzheimer's Disease: Genetics, Mechanisms and Therap...

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中国神经科学学会第十二届全国学术会议

作者： Lan Tan Jin-Tai Yu Department of Neurology Qingdao Municipal Hospital Qingdao University

Triggering receptor expressed on myeloid cells(TREMs) receptors constitute a family modulator in human innate immunity system that encode by a gene cluster, including TREM1、TREM2、TLT-1 and TLT-2. Two recent studies have identified that a rare coding variant(p. R47 H) in exon 2 of TREM2 gene increases susceptibility to lateonset Alzheimer’s disease(LOAD) with an odds ratio similar to that of the apolipoprotein E ε4 allele in Caucasian population, suggesing TREM2 represents an important susceptibility gene for LOAD. We then resequenced all exons of TREM2 and provided the first evidence that a rare coding variant(p.H157 Y) in TREM2 exon 3 conferred a considerable risk of AD with an odds ratio of 11.01. Furthermore, we decipher the expression and biologic functions of TREM2 under AD context. We showed that TREM2 was upregulated in microglia during disease progression. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ(1-42) phagocytosis and inhibited Aβ(1-42)-triggered proinflammatory responses. Besides, TREM2 overexpression rescued spatial cognitive impairments and ameliorated neuropathologies by suppressing neuroinflammation and subsequently attenuating tau kinase activity. For the first time, we declare the crucial role of TREM2 in AD pathogenesis. More importantly, overexpression of TREM2 in the brain of APPswe/PS1 d E9 mice/P301 S mice markedly ameliorated AD-related neuropathology including Aβ deposition, tau hyperphosphorylation, neuroinflammation, neuronal and synaptic losses. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a novel potential therapeutic target for this disease. At the same time, rs6910730, an intronic variant of TREM1, is associated with an increased Aβ neuropathology in the brains of elderly subjects. We further provided evidence that rs6910730 reduced the ability of human monocytes

关键词： Alzheimer’s disease TREM1 TREM2 rare variant Aβ Tau phosphorylation Therapeutic target

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