Genetic Epidemiology of Complex Traits

复杂性状的遗传流行病学

• 批准号: 9152727
• 负责人: Joan Ellen Bailey-Wilson
• 金额: $ 74.72万
• 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/9152727
• 关键词: Address; Admixture; Affect; African American; Age related macular degeneration; Alleles; Annual Reports; Asians; Astigmatism; Autistic Disorder; Award; Bipolar Disorder; Child; Cholesterol; Cleft Palate; Clinical; Collaborations; Collection; Complex; Crohn' s disease; DNA Methylation; Data; Data Analyses; Data Set; Development; Disease; Doctor of Philosophy; Environmental Risk Factor; Ethics; Etiology; European; Eye; Family; Family Study; Food Interactions; Frequencies; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genotype; Goals; HIV; Hepatic Vein Thrombosis; Human; Hyperopia; Individual; Institutes; International; Laboratories; Lipids; Manuscripts; Measures; Meta-Analysis; Metabolic; Methods; Myopia; National Human Genome Research Institute; National Institute of Child Health and Human Development; National Institute of Mental Health; Neurologic; Niemann-Pick Diseases; Paper; Parents; Pathway interactions; Patients; Phenotype; Physiologic Intraocular Pressure; Population; Preparation; Public Health Schools; Publications; Publishing; Pyridoxal Phosphate; Questionnaires; Refractive Errors; Research; Risk; Risk Factors; Role; Russia; Sardinia; Scientist; Sequence Analysis; Siblings; Societies; Statistical Methods; Surveys; Susceptibility Gene; Syndrome; Syria; Time; United States National Institutes of Health; Variant; Visceral; Work; autism spectrum disorder; base; case control; cohort; data sharing; design; disorder risk; exome; exome sequencing; follow-up; follower of religion Jewish; gene environment interaction; gene interaction; genetic epidemiology; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; genome wide association study; hypocholesterolemia; improved; iron metabolism; medical schools; member; nutrition; oral cleft; painful neuropathy; population based; rare variant; trait; working group; young adult

A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations, resulting in numerous publications in the past. We have recently published results of a genome-wide association study (GWAS) of refractive error in the AREDS, KORA, Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia, with confirmation of the discoveries from these data in several other GWAS. During this year we have published similar analyses of myopia and hyperopia (1) and bipolar disorder (using the AREDs data as controls in a collaborative study) (2). Whole exome SNP array genotyping was performed in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We are analyzing these data using multiple approaches to detect rare variants that contribute to refractive error traits. This year we have published results from one of these datasets (3) evaluating ancestry and risk factors for age-related macular degeneration in a population isolate. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2. The collaborative analyses performed by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. Previously, we performed analyses on our AREDS, KORA and FES GWAS data for meta-analyses of refractive error by the CREAM consortium and were co-authors on multiple papers presenting these results. Dr. Bailey-Wilson is co-leading the CREAM study of astigmatism with Dr. Jeremy Guggenheim and our first astigmatism meta-analysis was published this year (4). We have also completed analyses of myopia on the AREDS data for the next CREAM meta-analysis and are also leading a second astigmatism meta-analysis. We have begun a new project with CREAM, whereby our group will recall all genotypes jointly across studies in CREAM that used the same Illumina Exome-chip genotyping platforms. This is expected to improve the quality of all the genotype calls for rare variants and will make a major contribution to all of the planned CREAM meta-analyses of exome-chip data. We have also contributed results from the FES study to a meta-analysis of intraocular pressure that was published this year (5). Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic and Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on studies of oral clefts. We have recently performed a study attempting to identify gene-gene interactions within the WNT pathway for nonsyndromic oral clefts (with or without cleft palate) using Asian and European trio data. This project used some methods newly developed by our group as part of another Annual Report and was published this year (6). We are currently analyzing whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees and a manuscript is under development. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for excess hypocholesterolemia in autistic individuals has been observed in some multiplex families 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. Whole exome sequence data for all of the families is now being analyzed. Since the data were sequenced over a long time period, we are recalling all the data together and analyses will be ongoing over the next year. We are also collaborating with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to analyze WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. All of these data have now been sequenced and analyses are underway. Utilizing the sequence data from this project as controls (along with othet datasets) we published a paper this year that estimated the frequency of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1 (7). 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 analyses have been completed in these families. Dr. Bailey-Wilson was awarded WES sequencing of these families through a competitive application to the National Intramural Sequencing Center (NISC) and WES analyses have just been completed in all of our families. Analyses of these data are ongoing, using methods available in Golden Helix SVS as well as methods developed in Dr. Bailey-Wilsons Section under another Annual Report. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study of healthy young adults. This work is ongoing; several papers are in preparation or under review. A paper presenting evidence of genetic variants that influence circulating pyridoxal 5-phosphate concentration was published this year (8). Dr. Claire Simpson, a Staff Scientist, and Dr. Bashira Charles, a Research Fellow, have continued their collaboration with Dr. Steve Brant of Johns Hopkins School of Medicine. They are analyzing GWAS data on 500 African American Crohn's Disease patients. Dr. Simpson has completed linkage analyses on 12 members of a Jewish Crohn's Disease pedigree and follow-up is ongling. She and Dr. Brant plan to perform exome sequencing, DNA methylation and RNASeq expression analysis in affected sib pairs from his collection of Jewish families with Crohn's Disease. Drs. Simpson and Charles are currenlty working on GWAS and admixture studies. Dr. Simpson was a coauthor this year on a paper characterizing genetic loci that affect risk of IBD in African-Americans (9). Dr. Simpson was also first author of a study of barriers and ethical challenges in genetic data sharing that was published this year, based on a questionnaire survey of members of the International Genetic Epidemiology Society (10). Dr. Simpson has also established a collaboration (independent of Dr. Bailey-Wilson) with Dr. Rebecca Schmidt, Dr. Kyoungmi Kim and Dr. Irva Hertz-Picciotto at UC Davis (ENIGMA - Exploring Nutrient Interactions with Genetics as Mechanisms for Autism Spectrum Disorder) to examine gene-environment interactions in their MARBLES and CHARGE studies. This work will study the interaction between nutrition and genetics in ASD etiology. All analyses will use previously measured genotype data from the Affymetrix population specific EUR array on approximately 1000 CHARGE children, 497 with ASD and 553 typically developing. All data cleaning is now complete and analyses are ongoing. Dr. Emily Holzinger this year published work that was an extension of her PhD studies, showing that genetic variation in iron metabolism is associated with neuropathic pain in HIV-infected patients (11). She has also continued working on a manuscript from her PhD work in which she developed a computationally efficient data analysis pipeline for identifying genetic interactions associated with quantitative lipid traits; this manuscript is currently under review.

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博士从4个人群中收集了近视的血统书，过去有许多出版物。我们最近发表了全基因组关联研究（GWAS）的结果，该研究在AREDS，KORA，Framingham Eye研究（FES），MESA研究和撒丁岛的OGP-Talana研究中，并确认了其他几个GWAS中这些数据的发现。在今年，我们发表了类似的近视和远视（1）和躁郁症的分析（在协作研究中使用AREDS数据作为对照）（2）。在所有近视研究家族，AREDS队列和另外4000个无关的个体中，进行了整个外显子SNP阵列基因分型。我们正在使用多种方法来分析这些数据，以检测有助于折射误差特征的稀有变体。今年，我们发布了其中一个数据集（3）评估祖先和年龄相关的黄斑变性的危险因素的结果（3）。 Bailey-Wilson博士也是Cream的领导者之一，这是一项针对折光错误性状的荟萃分析的国际联盟，并且是Cream Analysis工作组2的联合主席。由Cream执行的协作分析将增加能够检测出对常见的等位基因对量化误差的较小效应的量化特征和其关联临床疾病的效果。以前，我们对我们的AREDS，KORA和FES GWAS数据进行了分析，以通过奶油联盟对折射率的摩托律误差进行分析，并在为这些结果呈现这些结果的多个论文中是合着者。 Bailey-Wilson博士正在与Jeremy Guggenheim博士共同领导散散的奶油研究，我们的第一次Astigmatism荟萃分析于今年出版（4）。我们还完成了对下一个乳膏荟萃分析的AREDS数据的近视分析，并正在领导第二次散光荟萃分析。我们已经开始了一个新项目，我们的小组将回想起所有使用相同的Illumina Exome-Chip基因分型平台的乳霜中共同研究的基因型。预计这将提高所有基因型都需要稀有变体的质量，并将为所有计划中的外显芯数据的奶油荟萃分析做出重大贡献。我们还为今年发表的眼内压力荟萃分析提供了FES研究的结果（5）。 Bailey-Wilson博士正在与叙利亚阿拉伯共和国的Hasan Albacha-Hejazi博士和Johns Hopkins Bloomberg公共卫生学院的Terri Beaty博士合作，讨论口腔裂口研究。 我们最近进行了一项研究，试图使用亚洲和欧洲三重奏数据来鉴定非龙骨口腔裂口（有或没有裂口的）的Wnt途径中的基因 - 基因相互作用。该项目使用我们小组新开发的一些方法作为另一份年度报告的一部分，并于今年发表（6）。 我们目前正在分析我们多重谱系选定成员的全基因组和全基因组序列数据，并且正在开发手稿。 Bailey-Wilson博士正在与Drs合作。 NICHD/NIH的福布斯·波特（Forbes Porter）和肯尼迪·克里格（Kennedy Krieger Institute）的伊莱恩·蒂尔尼（Elaine Tierney）在自闭症基因研究中。在某些多元家庭中观察到了自闭症个体中过量降液脂酯血症的证据，并获得了导演办公室的特殊资金，并授予了对具有极端胆固醇值的自闭症患者进行全异位测序，并且具有自闭症或自闭症或自闭症谱系障碍（ASD）的兄弟姐妹，以搜索这种较大的与这种家族性自身的患者的稀有变体。现在正在分析所有家庭的整个外显子序列数据。由于数据是在很长一段时间内测序的，因此我们将共同召回所有数据，并且分析将在明年进行。我们还与Drs合作。 NIMH/NIH的Sue Swedo和Audrey Thurm分析了他们表现良好的亲子三人组和至少一个孩子受自闭症影响的家庭。现在所有这些数据已经进行了测序，并且正在进行分析。利用该项目的序列数据作为对照（以及Othet数据集），我们今年发表了一篇论文，该论文估算了未识别的内脏/神经系统晚期发作的Niemann-Pick病的频率，C1型（7）。 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。这些家庭已经完成了链接分析。贝利·威尔森（Bailey-Wilson）博士通过对国家壁内测序中心（NISC）的竞争申请（NISC）授予了这些家庭的WES测序，WES分析刚刚在我们的所有家庭中都完成。这些数据的分析是在另一份年度报告中使用Golden Helix SVS中可用的方法以及Bailey-Wilsons博士部分中开发的方法的分析。 Bailey-Wilson博士还与NHGRI的Larry Brody博士和NHGRI的Alexander Wilson博士合作，分析了健康年轻人三一研究中有关代谢性状的GWAS数据。这项工作正在进行中；几篇论文正在准备或正在审查中。今年发表了一篇论文的遗传变异证据，这些证据影响了循环的5-磷酸吡啶量5-磷酸盐浓度（8）。 参谋科学家克莱尔·辛普森（Claire Simpson）博士和研究研究员巴希拉·查尔斯（Bashira Charles）博士继续与约翰·霍普金斯医学院的史蒂夫·布兰特（Steve Brant）合作。他们正在分析500名非裔美国人克罗恩病患者的GWAS数据。辛普森博士已经完成了对犹太克罗恩病血统的12名成员的联系分析，随访正在进行。她和Brant博士计划在受影响的SIB成对的Crohn病患有克罗恩病的犹太家庭中进行外显子组测序，DNA甲基化和RNASEQ表达分析。博士。辛普森（Simpson）和查尔斯（Charles）正在研究GWAS和混合研究。辛普森（Simpson）博士今年是一份著名的遗传基因座的合着者，该论文影响了非裔美国人的IBD风险（9）。 辛普森博士还根据对国际遗传流行病学协会成员的问卷调查（10）的问卷调查，对今年发表的遗传数据共享障碍和道德挑战的第一作者（10）。 Simpson博士还与UC Davis的Rebecca Schmidt博士，Kyoungmi Kim博士和Irva Hertz-Picciotto博士建立了合作（独立于Bailey-Wilson博士），UC Davis（Enigma-探索了与遗传学的营养互动，探索营养互动，作为自动化学障碍的机制），以进行基因 - Envirment rophorment and Envirment rothiment rothorm insarm insarm insarm insarm insarm insarm insarm insarm insarm inarmarmarmarmarmarmarmarmarmarmarmarmarmar互动。这项工作将研究ASD病因中的营养与遗传学之间的相互作用。 所有分析将使用先前测量的基因型数据来自Affymetrix人群特定于EUR阵列的大约1000个电荷儿童，497个ASD和553个通常会发育。所有数据清洁现在都已完成，并且正在进行分析。 艾米莉·霍尔辛格（Emily Holzinger）博士今年发表了她的博士学位研究的延伸，表明铁代谢的遗传变异与HIV感染的患者的神经性疼痛有关（11）。她还继续从博士学位工作中研究手稿，在该手稿中，她开发了一种计算有效的数据分析管道，以识别与定量脂质性状相关的遗传相互作用；此手稿目前正在审查中。