Determining the causal links and clinical significance of rare genetic variants

确定罕见遗传变异的因果关系和临床意义

• 批准号: MR/R026408/1
• 负责人: Lucija Klaric
• 金额: $ 32.45万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR026408%2F1
• 关键词: Determining; causal; links; clinical; significance

GWAS have identified many common genetic variants associated with various traits and diseases. However most of the individual effects of common variants at the trait level are very small, requiring very large sample sizes (i.e. 10's of thousands) for detection, with associations found providing low accuracy predictions of an individual's liability to disease or outcomes after treatment. Genetic effects of common variants on intermediate phenotypes, such as gene expression or protein concentrations, are often much larger than those on traits and diseases and such associations are thus often detectable in smaller samples of hundreds or thousands of individuals. Combining information from large studies of disease outcomes and smaller transcriptomic or proteomic studies in a two-sample Mendelian randomisation study can be used to provide evidence for a causal path from DNA variation through gene expression to a disease outcome. Even so, the relatively small genetic effects of common variants on phenotypic traits make them difficult to study in the small functional studies feasible in the laboratory. Some genetic variants have larger genetic effects than those common variants detected by GWAS, but such variants are often kept at low frequency within individual pedigrees by natural selection as a consequence of their larger effects on individual fitness. Such variants are hence difficult to detect in cosmopolitan studies of unrelated individuals, but may become detectable in studies of pedigreed populations, especially where small founder population size and drift may enhance the frequency of otherwise rare variants. Nonetheless such variants are unlikely to be in LD with and hence captured by associations with SNPs on standard arrays. Rare variants of large effect are most likely to be located within or close to expressed genes. Hence using DNA sequence from the exome and adjacent regions is a good strategy to capture such variants. In this project we propose to link proteomic data with the exome variants to detect locally (i.e. cis) acting genetic effects on protein concentrations.

GWAS 已经鉴定出许多与各种性状和疾病相关的常见遗传变异。然而，性状水平上常见变异的大多数个体影响都非常小，需要非常大的样本量（即数十万）才能检测，并且发现的关联对个体对疾病的可能性或治疗后的结果提供了低准确度的预测。常见变异对中间表型（例如基因表达或蛋白质浓度）的遗传影响通常比对性状和疾病的影响大得多，因此通常可以在数百或数千个体的较小样本中检测到这种关联。将大型疾病结果研究和小型转录组或蛋白质组研究的信息结合到两个样本的孟德尔随机化研究中，可以为从 DNA 变异到基因表达到疾病结果的因果路径提供证据。即便如此，常见变异对表型性状的遗传影响相对较小，这使得它们很难在实验室可行的小型功能研究中进行研究。一些遗传变异比 GWAS 检测到的常见变异具有更大的遗传效应，但由于它们对个体适应性的影响更大，因此这些变异通常通过自然选择在个体谱系中保持较低的频率。因此，在对无关个体的世界性研究中很难检测到此类变异，但在对谱系种群的研究中可能会检测到，特别是在较小的创建群体规模和漂移可能会增加其他罕见变异的频率的情况下。尽管如此，此类变异不太可能与标准阵列上的 SNP 存在 LD 关系，因此不会被其捕获。大效应的罕见变异最有可能位于表达基因内或附近。因此，使用外显子组和邻近区域的 DNA 序列是捕获此类变异的好策略。在这个项目中，我们建议将蛋白质组数据与外显子组变异联系起来，以检测局部（即顺式）遗传对蛋白质浓度的影响。

项目成果

Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential.

• DOI: 10.3390/biomedicines8100410
• 发表时间: 2020-10-13
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Cvetko A;Kifer D;Gornik O;Klarić L;Visser E;Lauc G;Wilson JF;Štambuk T
• 通讯作者: Štambuk T

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

• DOI: 10.1038/s41588-022-01062-7
• 发表时间: 2022-05
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Howe, Laurence J.;Nivard, Michel G.;Morris, Tim T.;Hansen, Ailin F.;Rasheed, Humaira;Cho, Yoonsu;Chittoor, Geetha;Ahlskog, Rafael;Lind, Penelope A.;Palviainen, Teemu;van der Zee, Matthijs D.;Cheesman, Rosa;Mangino, Massimo;Wang, Yunzhang;Li, Shuai;Klaric, Lucija;Ratliff, Scott M.;Bielak, Lawrence F.;Nygaard, Marianne;Giannelis, Alexandros;Willoughby, Emily A.;Reynolds, Chandra A.;Balbona, Jared V.;Andreassen, Ole A.;Ask, Helga;Baras, Aris;Bauer, Christopher R.;Boomsma, Dorret I.;Campbell, Archie;Campbell, Harry;Chen, Zhengming;Christofidou, Paraskevi;Corfield, Elizabeth;Dahm, Christina C.;Dokuru, Deepika R.;Evans, Luke M.;de Geus, Eco J. C.;Giddaluru, Sudheer;Gordon, Scott D.;Harden, K. Paige;Hill, W. David;Hughes, Amanda;Kerr, Shona M.;Kim, Yongkang;Kweon, Hyeokmoon;Latvala, Antti;Lawlor, Deborah A.;Li, Liming;Lin, Kuang;Magnus, Per;Magnusson, Patrik K. E.;Mallard, Travis T.;Martikainen, Pekka;Mills, Melinda C.;Njolstad, Pal Rasmus;Overton, John D.;Pedersen, Nancy L.;Porteous, David J.;Reid, Jeffrey;Silventoinen, Karri;Southey, Melissa C.;Stoltenberg, Camilla;Tucker-Drob, Elliot M.;Wright, Margaret J.;Kweon, Hyeokmoon;Hewitt, John K.;Keller, Matthew C.;Stallings, Michael C.;Lee, James J.;Christensen, Kaare;Kardia, Sharon L. R.;Peyser, Patricia A.;Smith, Jennifer A.;Wilson, James F.;Hopper, John L.;Hagg, Sara;Spector, Tim D.;Pingault, Jean-Baptiste;Plomin, Robert;Havdahl, Alexandra;Bartels, Meike;Martin, Nicholas G.;Oskarsson, Sven;Justice, Anne E.;Millwood, Iona Y.;Hveem, Kristian;Naess, Oyvind;Willer, Cristen J.;Asvold, Bjorn Olav;Koellinger, Philipp D.;Kaprio, Jaakko;Medland, Sarah E.;Walters, Robin G.;Benjamin, Daniel J.;Turley, Patrick;Evans, David M.;Smith, George Davey;Hayward, Caroline;Brumpton, Ben;Hemani, Gibran;Davies, Neil M.
• 通讯作者: Davies, Neil M.

Variants associated with HHIP expression have sex-differential effects on lung function.

• DOI: 10.12688/wellcomeopenres.15846.2
• 发表时间: 2020
• 期刊: Wellcome open research
• 作者: Fawcett KA;Obeidat M;Melbourne C;Shrine N;Guyatt AL;John C;Luan J;Richmond A;Moksnes MR;Granell R;Weiss S;Imboden M;May-Wilson S;Hysi P;Boutin TS;Portas L;Flexeder C;Harris SE;Wang CA;Lyytikäinen LP;Palviainen T;Foong RE;Keidel D;Minelli C;Langenberg C;Bossé Y;Van den Berge M;Sin DD;Hao K;Campbell A;Porteous D;Padmanabhan S;Smith BH;Evans DM;Ring S;Langhammer A;Hveem K;Willer C;Ewert R;Stubbe B;Pirastu N;Klaric L;Joshi PK;Patasova K;Massimo M;Polasek O;Starr JM;Karrasch S;Strauch K;Meitinger T;Rudan I;Rantanen T;Pietiläinen K;Kähönen M;Raitakari OT;Hall GL;Sly PD;Pennell CE;Kaprio J;Lehtimäki T;Vitart V;Deary IJ;Jarvis D;Wilson JF;Spector T;Probst-Hensch N;Wareham NJ;Völzke H;Henderson J;Strachan DP;Brumpton BM;Hayward C;Hall IP;Tobin MD;Wain LV
• 通讯作者: Wain LV

Genetic Regulation of Immunoglobulin G Glycosylation.

• DOI: 10.1007/978-3-030-76912-3_8
• 发表时间: 2021-01-01
• 期刊: Experientia supplementum (2012)
• 作者: Frkatovic, Azra;Zaytseva, Olga O;Klaric, Lucija
• 通讯作者: Klaric, Lucija

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

孤立的苏格兰人群中超罕见变异负载的增加影响外显子和监管区域

• DOI: 10.1101/809244
• 发表时间: 2019
• 作者: Halachev M