Genetic Epidemiology of Complex Traits

复杂性状的遗传流行病学

• 批准号: 8149438
• 负责人: Joan Ellen Bailey-Wilson
• 金额: $ 77.03万
• 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/8149438
• 关键词: 11q22; 12p; 1p34; Address; Affect; African; Age; Alleles; Amish; Aneurysm; Ashkenazim; Attention deficit hyperactivity disorder; Authorization documentation; Autistic Disorder; Candidate Disease Gene; Complex; Data; Data Collection; Disease; Enrollment; Etiology; Eye; Family; Frequencies; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genotype; Germany; Glaucoma; Goals; Hepatic Vein Thrombosis; Human; Hyperopia; Individual; International; Laboratories; Lasers; Metalloproteinase Gene; Methods; Microsatellite Repeats; Mutation; Myopia; National Human Genome Research Institute; National Institute of Child Health and Human Development; Neurologic; Nuclear Family; Ophthalmic examination and evaluation; Osteogenesis Imperfecta; Paper; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Primary Angle Closure Glaucoma; Public Health Schools; Publications; Publishing; Questionnaires; Refractive Errors; Research; Research Design; Risk; Role; Russia; Sclerosis; Siblings; Smoking; Stroke; Syndrome; Syria; United States National Institutes of Health; Universities; Variant; Wisconsin; Work; autism spectrum disorder; base; follow-up; follower of religion Jewish; genetic epidemiology; genetic pedigree; hypocholesterolemia; trait

Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein and Sudha Iyengar on analyses of existing family data from the Beaver Dam Eye Study (BDES). 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. Linkage analyses using a new SNP linkage panel with multiple traits including: refraction, myopia, nuclear sclerosis, etc are underway. Dense SNPs for finemapping of Chromosome 19 for IOP and 2 smaller glaucoma-associated regions on chromosomes 5 and 6 are currently underway. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 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 analyses confirmed our previous linkage of a QTL for refractive error on 1p34-p36. During follow-up of our previous chromosome 22 linkage results for myopia, we have used association and sequencing methods to narrow the region to 3 candidate loci. We are carefully examining these candidates to determine which is the susceptibility locus and are currently performing additional extensive deep sequencing of this region. We found significant evidence of linkage of refractive error to chromosome 7q in the African-American pedigrees and are analyzing a finemapping panel of SNPs to follow-up this region. This year we published evidence of association of matrix metalloproteinase gene polymorphisms with refractive error in our Amish and Ashkenazi family data (4). Drs. Stambolian, Bailey-Wilson and Thomas Meitinger (Germany) are collaborating to perform a GWAS of refractive error in the AREDS and KORA population cohorts and genotyping is underway. Dr. Bailey-Wilson is also leading an international consortium on meta-analysis of refractive error and related traits which will increase power to detect common alleles with small effects on this eye trait and its related disorders, myopia and hyperopia. 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 over 500,000 SNPs and 600 microsatellite marker loci. Genomewide linkage and association analyses of traits related to myopia and hyperopia, refractive error and glaucoma related traits (IOP, Cup-to Disc, Glaucoma) are ongoing. 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-Wilson's 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. One candidate gene has been identified and a paper reporting evidence that a variant in the iatrophilin 3 gene contributes to risk of ADHD and predicts effectively of stimulant medication was published this year (1). 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 and more genotyping will be performed when enrollment of a total of 50 families informative for linkage is completed. We have also applied for funding of whole-exome sequencing of selected members of these unique pedigrees and will pursue this avenue of research if funds become available. 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 and additional family data are being collected. Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. This study is ongoing and we are seeking funding to extend our study to autistic patients with extreme hypocholesterolemia but who do not have siblings affected with ASD. Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage and family-based association analyses are underway in these families. Dr. Bailey-Wilson also serves in an advisory role on study design and interpretation of results for the Familial Intracranial Aneurysm (IA) consortium. This consortium is using both linkage and genome-wide association methods to detect genetic predisposition to this type of familial strokes. Results of a 6000 SNP genome-wide linkage study previously yielded evidence for linkage of IA on chromosome 4q and chromosome 12p. Significant evidence for a gene x smoking interaction was detected on chromosome 7p. These results suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms. Linkage analysis using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, showed evidence for linkage on chromosomes 11 and 6, which supports the concept of shared genetic risk for these different types of aneurysm. We are now pursuing a genome-wide association study to attempt to identify common alleles of small effect that may contribute to risk of this disorder. This year we have published results showing a relationship between smoking and replicated sequence variants in intracranial aneurysm (2). Dr. Bailey-Wilson also collaborates with Dr. Joan Marini of NICHD on studies of mutation age in a rare disorder, Lethal Recessive Type VIII Osteogenesis Imperfecta, in West Africans and African Americans. A manuscript is under review reporting these results. Dr. Bailey-Wilson also served in an advisory capacity to Dr. Ching-Yu Cheng, a Special Volunteer in the Statistical Genetics Section, on a study of primary angle-closure glaucoma, resulting in a publication on structure-function correlations using scanning laser polarimetry in this disorder (3).

Bailey-Wilson博士正在与Drs合作。芭芭拉（Barbara）和罗纳德·克莱因（Ronald Klein）和苏达·艾扬格（Sudha Iyengar）对海狸大坝眼研究（BDES）的现有家庭数据分析。威斯康星州海狸大坝城镇和乡镇的私人人口普查都进行了，所有人都要求参加大量的眼睛检查，并要求填写一份调查环境风险因素暴露的问卷。我们以前已经在整个海狸大坝群体上分析了全面基因组扫描（GWS）的数据，用于青光眼，IOP，折射率，近视，近视，近视和各种形式的白内障。使用新的SNP链接面板进行了连锁分析，其中包括：折射，近视，核硬化症等。 目前正在进行染色体5和6上染色体19号染色体19的密集SNP和2个较小的青光眼相关区域。 对德怀特·斯托莫利亚博士的近视遗传学的研究正在进行中。 Stambolian博士已从4个人群中收集了近视的血统书。 Ashkenazi犹太人和阿米什人家庭中屈光不正的分析揭示了染色体上有QTL的证据。在我们的Ashkenazi和Amish家族中，对一组约1500个SNP进行了基因分型，以跟进染色体1上的折光性错误的链接。这些分析证实了我们先前在134-P36上折射误差的QTL的链接。在对以前的近视染色体22连杆结果的随访期间，我们使用关联和测序方法将区域范围缩小到3个候选基因座。我们正在仔细检查这些候选者，以确定哪个是易感性基因座，目前正在对该区域进行额外的深入测序。我们发现了在非裔美国人的血统中与7q染色体7Q折射误差连接的重要证据，并正在分析一组SNP来跟进该区域。今年，我们发表了基质金属蛋白酶基因多态性与我们的阿米什人和阿什凯纳济家族数据中折射错误的相关性证据（4）。博士。 Stambolian，Bailey-Wilson和Thomas Meitinger（德国）正在合作，在AREDS和KORA人口同伙中进行屈光不正的GWA，并且正在进行基因型。贝利·威尔森（Bailey-Wilson）博士还领导着屈光不正和相关特征的荟萃分析的国际联盟，这将增加检测到这种眼性状及其相关疾病（近视和近视）的常见等位基因的能力。 Bailey-Wilson博士及其小组的几名成员已获得从Framingham Eye研究和后代研究队列中分析遗传数据的许可。该样品由约1100个核心家庭组成，其成员已被广泛表型，并为500,000多个SNP和600个微卫星标记基因座进行了基因分型。与近视和绩效相关的性状，折射误差和青光眼相关性状（IOP，Cup-to Disc，青光眼）的特征，全基因组的联系和关联分析正在进行中。 Bailey-Wilson博士是与DRS合作的注意力缺陷多动障碍的合作研究。 NHGRI的Max Muenke和Mauricio Arcos-Burgos博士和哥伦比亚的Antioquia大学。 Bailey-Wilson博士的作用是帮助研究设计，并为该项目提供统计遗传学家的建议。全基因组扫描基因分型和链接分析已在第一组家庭中完成，随后进行了限制。我们先前已经显示了多动症与20132年4Q333、11q22和17p11连接的证据。已经进行了关联研究以跟进我们的联系结果，并在其他样本中复制了重要的关联。已经确定了一个候选基因，并报告了一份报道证据，表明雌激素3基因的变体有助于ADHD的风险，并在今年发表了有效地预测兴奋剂药物的风险（1）。 Bailey-Wilson博士正在与叙利亚阿拉伯共和国的Hasan Albacha-Hejazi博士合作，波士顿大学的Diego Wyszynski博士和Johns Hopkins公共卫生学院的Terri Beaty博士在口头裂口上进行了链接研究。叙利亚阿拉伯共和国正在进行数据收集，当总共有50个家庭提供联系以实现联系时，将进行更多的基因分型。我们还申请了这些独特的谱系选定成员的全外观测序资金，如果有资金可用，将追求这一研究途径。 Bailey-Wilson博士正在与Drs合作。 NIH的福布斯·波特（Forbes Porter）和肯尼迪·克里格（Kennedy Krieger）的伊莱恩·蒂尔尼（Elaine Tierney）对自闭症的基因研究。已经发现自闭症患者与降降血液脂酯血症联系的证据。正在进行其他数据中的确认，并正在收集其他家庭数据。寻求主任办公室的特殊资金，并授予对具有极端胆固醇价值的自闭症患者的自闭症患者以及患有自闭症或自闭症谱系障碍（ASD）的兄弟姐妹进行全外观测序，以搜索该家族自闭症/ASD患者的这一子集中的稀有变体。这项研究正在进行中，我们正在寻求资金将我们的研究扩展到极端降临素血症的自闭症患者，但对ASD的兄弟姐妹没有影响。 Bailey-Wilson博士正在与John Heiss博士合作，研究俄罗斯的Chiari综合症研究。在那里的几个大型家族中，这种罕见的神经系统综合征在频率增加时观察到。这些家庭正在进行联系和基于家庭的协会分析。 贝利·威尔森（Bailey-Wilson）博士还在研究设计和解释颅内动脉瘤（IA）财团的结果方面发挥了咨询作用。该财团同时使用联系和全基因组关联方法来检测对这种类型的家族性中风的遗传易感性。 6000个SNP全基因组连锁研究的结果先前提供了IA在4q和12p染色体染色体上连接的证据。在7p染色体上检测到了基因X吸烟相互作用的大量证据。这些结果表明，在大多数IA家族中，不太可能有一个单一的常见变体。相反，多种遗传和环境风险因素可能导致颅内动脉瘤的易感性。使用最广泛的疾病表型的连锁分析，包括IA，腹部AA和胸腔AA，显示了染色体11和6上连接的证据，这支持了这些不同类型的动脉瘤的共同遗传风险的概念。我们现在正在进行一项全基因组协会研究，以试图确定可能导致这种疾病风险的小效应的常见等位基因。今年，我们发布了结果，显示了颅内动脉瘤中吸烟与复制序列变体之间的关系（2）。 Bailey-Wilson博士还与NICHD的Joan Marini博士合作，涉及罕见疾病，致命的隐性型VIII型成骨的研究，西非人和非洲裔美国人。手稿正在审查中报告这些结果。 贝利·威尔森（Bailey-Wilson）博士还为统计遗传学部分的特殊志愿者Ching-Yu博士（Ching-Yu Cheng）博士提供了咨询能力，该研究对原发性角度闭合青光眼的研究研究，导致了该疾病中使用扫描激光极化的结构函数相关性的出版物（3）。