Genetic Epidemiology of Complex Traits

复杂性状的遗传流行病学

• 批准号: 7594335
• 负责人: Joan Ellen Bailey-Wilson
• 金额: $ 80.5万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594335
• 关键词: 11q22; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; African American; Age; Alleles; Amebiasis; Amish; Animal Model; Archives; Ashkenazim; Attention deficit hyperactivity disorder; Authorization documentation; Autistic Disorder; Baltimore; Bangladesh; Boston; Brazil; CD4 Lymphocyte Count; CUL5 gene; Calculi; Candidate Disease Gene; Canis familiaris; Castor; Cataract; Caucasians; Caucasoid Race; Causations; Censuses; Child; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 5; Class; Code; Cohort Studies; Collaborations; Communicable Diseases; Complex; Congenital Abnormality; Cryptosporidium; Data; Data Analyses; Data Collection; Developmental Gene; Disease; Enrollment; Entamoeba histolytica; Environmental Risk Factor; Eye; Family; Folate; Folic Acid; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genotype; Glaucoma; Goals; Haplotypes; Human; Hyperopia; Immune response; Individual; Infection; Injecting drug user; Interferon Type II; Intestines; Intravenous; Iowa; Laboratories; Leishmania; Letters; Link; Live Birth; Malnutrition; Manuscripts; Maryland; Measures; Methods; Microsatellite Repeats; Myopia; Neural Tube Defects; Nuclear; Nuclear Family; Ophthalmic examination and evaluation; Ophthalmology; Paper; Parasites; Parents; Pathway interactions; Pattern; Phenotype; Phlebotominae; Population; Postdoctoral Fellow; Predisposition; Preparation; Prevalence; Public Health Schools; Published Comment; Publishing; Quantitative Trait Loci; Questionnaires; Receptor Gene; Refractive Errors; Research Design; Risk; Role; Sampling; Scanning; Sclerosis; Statistical Methods; Syria; Testing; United States National Institutes of Health; Universities; Variant; Virginia; Visceral Leishmaniasis; Vitamin B 12; Wisconsin; Work; base; case control; cohort; design; disorder risk; experience; follow-up; follower of religion Jewish; genetic analysis; genetic epidemiology; genetic linkage analysis; genetic pedigree; genome wide association study; genome-wide linkage; hypocholesterolemia; leptin receptor; member; mouse model; oral cleft; segregation; trait

Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein on analyses of existing family data from the Beaver Dam Eye Study. A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. We have previously analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. We published 2 manuscripts in Archives of Ophthalmology this year detailing our linkage results for myopia/hyperopia and IOP/glaucoma, a letter to the editor is in press that highlights a possible combined glaucoma/high IOP risk locus, and a commentary on our glaucoma work was highlighted in JAMA (Pasquale et al, 2007). Genotyping for a SNP linkage panel was just completed at CIDR and will be released shortly. This will give us increased power for linkage with multiple traits including: refraction, myopia, nuclear sclerosis, etc. Dense SNPs for finemapping of Chromosome 19 for IOP and 2 smaller glaucoma-associated regions on chromosomes 5 and 6 will be genotyped and analyzed in the next fiscal year. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 5 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1. A set of about 1500 SNPs were genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1; these data analyses are ongoing. New families have been genotyped for a genome wide scan and a paper presenting confirmation of our previous chromosome 22 linkage results for myopia in these new Ashkenazi families has been published. Two papers describing our myopia and refractive error linkage results in a set of African-American families and a set of Caucasian familes are in preparation. Dr. Bailey-Wilson and several members of her group have received permission to analyze genetic data from the Framingham Eye Study and Offspring Study cohorts. The sample consists of about 1100 nuclear families whose members have been phenotyped extensively and genotyped for 116,000 SNPs and 600 microsatellite marker loci. Genomewide linkage and association analyses of traits related to myopia and hyperopia have begun in this fiscal year and next year we will begin similar analyses of the glaucoma related traits (IOP, Cup-to Disc, Glaucoma). Dr. Bailey-Wilson is advising Dr. Arash Etemadi on familial aggregation and segregation analyses of family data from the Tehran Eye Study. A paper was published this year showing strong patterns of aggregation of myopia in this population, consistent with other populations around the world. Segregation analyses are ongoing. Drs. Wojciechowski and Bailey-Wilson have started a new collaboration with Drs. Chris Murphy, Donald Mutti and Edwin Stone on a study of myopia in English springer spaniel dogs, a model organism for human myopia. Dr. Stones laboratory will perform genotyping using a recently developed SNP chip for dogs, and we will perform the analyses. Dr. Bailey-Wilson is a member of a collaborative study of Attention Deficit Hyperactivity Disorder, collaborating with Drs. Max Muenke and Dr. Mauricio Arcos-Burgos of NHGRI and University of Antioquia, Columbia. Dr. Bailey-Wilsons role is to help with study design and to serve as advising statistical geneticist on the project. Genome-wide scan genotyping and linkage analysis has been completed on the first set of families followed by finemapping. We have previously shown evidence of linkage of ADHD to 4q132, 5q333, 11q22, and 17p11. Association studies have been performed to follow up our linkage results, and significant associations have been replicated in additional samples. Papers are in preparation. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic, Dr. Diego Wyszynski of Boston University and Dr. Terri Beaty of Johns Hopkins School of Public Health on a linkage study of oral clefts. Data collection is ongoing in the Syrian Arab Republic. New Syrian families have been genotyped for genome-wide scan markers and analyses of these data are ongoing. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NIH and Elaine Tierney of Kennedy Krieger on a genetic study of autism. Evidence for linkage of autistic individuals with hypocholesterolemia has been found. Confirmation in additional data is underway. Another set of projects led by Dr. Priya Duggal, a senior postdoctoral trainee in the Section, encompass the human genetic predisposition to infectious diseases including Visceral leishmaniasis, Amebiasis and HIV/AIDS. Dr. Duggal collaborates with Dr. Mary Wilson of the University of Iowa and Dr. Selma Jeronimo of Natal, Brazil on the study of Visceral leishmaniasis (VL). VL is a potentially fatal disease caused by the protozoan Leishmania chagasi that is carried by the sandfly. We have completed a genome wide linkage scan for the DTH immune response, and the manuscript (Jeronimo et al is in press at JID). We are currently choosing a panel of 7600 SNPs to finemap the regions in and around our linkage peaks. Dr. Duggal collaborates with Dr. William Petri of the University of Virginia and Dr. Rashidul Haque at the ICDDR,B, Dhaka, Bangladesh on the host susceptibility to Amebiasis. Amebiasis is a large contributor to diarrheal disease in the developing world, and is caused by infection of the intestine by the parasite Entamoeba histolytica. This past year we published a manuscript on IFN-g and malnutrition and stunting in our cohort of children (Haque et al. AJTMH 2007). In addition, we identified an association with HLA class II alleles and cryptosporidium, another cause of diarrheal disease in these children (Kirkpatrick et al., in press JID) and another is under review. We have genotyped tagging SNPs in 90 candidate genes for 450 children in this study. Of the 20 genes already analyzed, we have identified a strong association with a functional coding SNP in the Leptin Receptor gene. Dr. Duggal also aims to understand genetic host susceptibility to HIV/AIDS, using a cohort of 3000 injection drug users in Baltimore, Maryland that participate in the AIDS Link to Intravenous Experience (ALIVE). Part of the APOBEC compex is the CUL5 factor; we have identified a cluster of haplotypes driven by 3 SNPs that influences progression to AIDS, and also has a strong influence on CD4 cell counts. There is also a strong additive interaction with our previous finding in APOBEC3G. A paper was published earlier this year in PLOS genetics (An et al, 2007). Another project, led by Dr. Elizabeth Gillanders, a postdoctoral fellow in the section, is a collaborative study of Neural Tube Defects (NTDs) with Dr. Larry Brody of NHGRI. NTDs are one of the most common birth defects with a prevalence of about 1/1000 live births. NTSs are known to have a large genetic component and to often be preventable by folic acid therapy. We analyzed a 1536 SNPs in 83 candidate genes selected from the folate/vitamin B12 pathway, genes involved in transport of folate or vitamin B12 and genes implicated in NTD risk from mouse models (transcription or developmental genes) in about 300 NTD cases and their parents and in about 300 Irish unaffected controls. We have performed case-control and family-based tests of association. Additional analyses are ongoing.

Bailey-Wilson 博士正在与 Drs 合作。芭芭拉（Barbara）和罗纳德·克莱因（Ronald Klein）对海狸坝眼科研究的现有家庭数据进行了分析。对威斯康星州海狸坝镇和乡镇进行了一次私人人口普查，所有年龄在 43 至 84 岁之间的个人都被要求参加，接受广泛的眼部检查，并要求填写一份测量环境风险因素暴露的调查问卷。我们之前分析了 Beaver Dam 整个家庭队列的 STRP 全基因组扫描 (GWS) 数据，包括青光眼、眼压、屈光不正、近视、远视和各种形式的白内障。今年，我们在眼科档案中发表了两篇手稿，详细介绍了我们对近视/远视和 IOP/青光眼的关联结果，一封致编辑的信已出版，其中强调了可能的青光眼/高 IOP 风险位点，以及对我们青光眼工作的评论JAMA 中强调了这一点（Pasquale 等人，2007 年）。 CIDR 刚刚完成了 SNP 连锁面板的基因分型，并将很快发布。这将为我们提供与多种性状关联的增强能力，包括：屈光、近视、核硬化等。用于 IOP 的 19 号染色体精细定位的密集 SNP 以及 5 号和 6 号染色体上 2 个较小的青光眼相关区域将在基因分型中进行基因分型和分析。下一个财政年度。 德怀特·斯坦博利安 (Dwight Stambolian) 博士正在进行一项近视遗传学研究。 Stambolian 博士收集了 5 个人群的近视谱系。对德系犹太人和阿米什家族屈光不正的分析揭示了 1 号染色体上存在 QTL 的证据。在我们的德系犹太人和阿米什家族中对一组约 1500 个 SNP 进行了基因分型，以追踪 1 号染色体上屈光不正的关联；这些数据分析正在进行中。新的家族已经进行了全基因组扫描的基因分型，并且发表了一篇论文，证实了我们之前在这些新的德系犹太人家族中近视的 22 号染色体连锁结果。两篇描述近视和屈光不正在一组非洲裔美国家庭和一组白人家庭中的关联结果的论文正在准备中。 Bailey-Wilson 博士和她的团队的几位成员已获准分析弗雷明汉眼科研究和后代研究队列的遗传数据。该样本由约 1100 个核心家族组成，其成员已进行了广泛的表型分析，并针对 116,000 个 SNP 和 600 个微卫星标记位点进行了基因分型。本财年已开始对近视和远视相关特征进行全基因组连锁和关联分析，明年我们将开始对青光眼相关特征（眼压、视盘到视盘、青光眼）进行类似分析。 Bailey-Wilson 博士正在为 Arash Etemadi 博士就德黑兰眼科研究的家庭数据进行家族聚集和分离分析提供建议。今年发表的一篇论文显示了该人群近视的强烈聚集模式，这与世界其他人群的情况一致。隔离分析正在进行中。 博士。 Wojciechowski 和 Bailey-Wilson 已与 Drs. 开始了新的合作。克里斯·墨菲 (Chris Murphy)、唐纳德·穆蒂 (Donald Mutti) 和埃德温·斯通 (Edwin Stone) 对英国史宾格犬（人类近视的模型生物）的近视进行了研究。 Stones 博士实验室将使用最近开发的狗 SNP 芯片进行基因分型，我们将进行分析。 Bailey-Wilson 博士是注意力缺陷多动障碍合作研究的成员，与 Drs. 合作。 NHGRI 和哥伦比亚安蒂奥基亚大学的 Max Muenke 和 Mauricio Arcos-Burgos 博士。 Bailey-Wilsons 博士的职责是帮助研究设计并担任该项目的统计遗传学家建议。第一组家族的全基因组扫描基因分型和连锁分析已完成，随后进行了精细定位。我们之前已经展示了 ADHD 与 4q132、5q333、11q22 和 17p11 关联的证据。已进行关联研究以跟踪我们的关联结果，并且已在其他样本中复制了显着的关联。论文正在准备中。 Bailey-Wilson 博士正在与阿拉伯叙利亚共和国的 Hasan Albacha-Hejazi 博士、波士顿大学的 Diego Wyszynski 博士和约翰霍普金斯大学公共卫生学院的 Terri Beaty 博士合作开展口腔裂的关联研究。阿拉伯叙利亚共和国正在收集数据。已经对新的叙利亚家庭进行了全基因组扫描标记的基因分型，并且正在对这些数据进行分析。 贝利-威尔逊博士正在与博士一起工作。美国国立卫生研究院的福布斯·波特和肯尼迪·克里格的伊莱恩·蒂尔尼关于自闭症的遗传学研究。已经发现自闭症患者与低胆固醇血症存在联系的证据。其他数据的确认正在进行中。 该科高级博士后实习生 Priya Duggal 博士领导的另一组项目涉及人类对传染病的遗传倾向，包括内脏利什曼病、阿米巴病和艾滋病毒/艾滋病。 Duggal 博士与爱荷华大学的 Mary Wilson 博士合作， 巴西纳塔尔的 Selma Jeronimo 博士从事内脏利什曼病 (VL) 的研究。 VL 是一种潜在致命的疾病，由白蛉携带的原生动物恰加斯利什曼原虫引起。我们已经完成了 DTH 免疫反应的全基因组连锁扫描和手稿（Jeronimo 等人正在 JID 上印刷）。我们目前正在选择一组 7600 个 SNP 来精细绘制连锁峰内部和周围的区域。 Duggal 博士与弗吉尼亚大学的 William Petri 博士和孟加拉国达卡 ICDDR,B 的 Rashidul Haque 博士合作研究宿主对阿米巴病的易感性。阿米巴病是发展中国家腹泻病的主要原因，是由溶组织内阿米巴寄生虫感染肠道引起的。去年，我们发表了一篇关于 IFN-g 与我们的儿童群体营养不良和发育迟缓的手稿（Haque 等人，AJTMH 2007）。此外，我们还发现了 HLA II 类等位基因和隐孢子虫之间的关联，隐孢子虫是这些儿童腹泻病的另一个原因（Kirkpatrick 等人，JID 报刊），另一个原因正在审查中。在这项研究中，我们对 450 名儿童的 90 个候选基因中的 S​​NP 进行了基因分型。在已经分析的 20 个基因中，我们发现与瘦素受体基因中的功能编码 SNP 存在很强的关联。 Duggal 博士还利用马里兰州巴尔的摩市参与 AIDS Link to Intravenous Experience (ALIVE) 的 3000 名注射吸毒者组成的队列，了解宿主对 HIV/AIDS 的遗传易感性。 APOBEC 综合体的一部分是 CUL5 因子；我们已经鉴定出一组由 3 个 SNP 驱动的单倍型，这些单倍型影响 AIDS 的进展，并且对 CD4 细胞计数也有很大影响。与我们之前在 APOBEC3G 中的发现也存在很强的相加相互作用。今年早些时候，PLOS Genetics 上发表了一篇论文（An et al, 2007）。 另一个项目由该部门的博士后研究员 Elizabeth Gillanders 博士领导，是与 NHGRI 的 Larry Brody 博士合作研究神经管缺陷 (NTD)。 NTD 是最常见的出生缺陷之一，其患病率约为 1/1000 的活产婴儿。众所周知，NTS 具有很大的遗传成分，并且通常可以通过叶酸治疗来预防。我们分析了 83 个候选基因中的 1536 个 SNP，这些候选基因选自叶酸/维生素 B12 途径、参与叶酸或维生素 B12 运输的基因以及与 NTD 风险有关的基因，这些基因来自约 300 个 NTD 病例及其父母的小鼠模型（转录或发育基因）以及大约 300 个爱尔兰未受影响的控制区。我们进行了病例对照和基于家庭的关联测试。其他分析正在进行中。