Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk.
Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk.
复制标题
DOI：
10.1016/j.ebiom.2022.104356
复制
发表时间：
2022-12
期刊：
影响因子：
11.1
通讯作者：
DEMISTIFI Consortium
中科院分区：
文献类型：
--
作者：
Mohammadi-Nejad, Ali-Reza;Allen, Richard J.;Kraven, Luke M.;Leavy, Olivia C.;Jenkins, R. Gisli;V. Wain, Louise;Auer, Dorothee P.;Sotiropoulos, Stamatios N.;DEMISTIFI Consortium
特发性肺纤维化（IPF）是一种严重的肺实质疾病。它具有已知的多基因风险，迄今为止至少涉及基因组的17个区域。越来越多的证据表明，特发性纤维化的多发病与神经退行性疾病或情感障碍有关。然而，到目前为止，还没有研究明确探讨IPF、相关遗传风险特征和特定大脑特征之间的联系。我们利用了来自英国生物银行人群水平资源的32，000多名参与者的成像和遗传数据，以探索IPF遗传风险与成像衍生的脑内表型之间的联系。我们在17种已知IPF风险变异和1248种多模态成像衍生特征之间进行了全脑成像-遗传学关联研究，这些特征描述了大脑结构和功能。我们确定了皮质形态学特征、白色物质微结构和17号染色体（17 q21.31）和8号染色体（DEPTOR）中IPF风险位点之间的强相关性。通过共定位分析，我们证实了前扣带回皮质厚度和更广泛的白色物质微结构变化与8号染色体位点的IPF共享一个单一的因果变异。事后初步分析表明，用力肺活量可能部分介导DEPTOR变异和白色物质显微结构之间的关联，但不是DEPTOR风险变异和皮质厚度之间的关联。我们的研究结果揭示了IPF遗传风险与大脑结构差异之间的相关性，包括皮质和白色物质。组织特异性成像特征的差异表明，在已知DEPTOR高表达的区域中存在局灶性皮质变薄的不同潜在机制，与肺功能无关，并且更广泛的微结构白色物质变化与缺氧或神经炎症一致，可能由肺功能介导。这项研究得到了NIHR诺丁汉生物医学研究中心和英国医学研究理事会的支持。
Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung parenchyma. It has a known polygenetic risk, with at least seventeen regions of the genome implicated to date. Growing evidence suggests linked multimorbidity of IPF with neurodegenerative or affective disorders. However, no study so far has explicitly explored links between IPF, associated genetic risk profiles, and specific brain features. We exploited imaging and genetic data from more than 32,000 participants available through the UK Biobank population-level resource to explore links between IPF genetic risk and imaging-derived brain endophenotypes. We performed a brain-wide imaging-genetics association study between the presence of 17 known IPF risk variants and 1248 multi-modal imaging-derived features, which characterise brain structure and function. We identified strong associations between cortical morphological features, white matter microstructure and IPF risk loci in chromosomes 17 (17q21.31) and 8 (DEPTOR). Through co-localisation analysis, we confirmed that cortical thickness in the anterior cingulate and more widespread white matter microstructure changes share a single causal variant with IPF at the chromosome 8 locus. Post-hoc preliminary analysis suggested that forced vital capacity may partially mediate the association between the DEPTOR variant and white matter microstructure, but not between the DEPTOR risk variant and cortical thickness. Our results reveal the associations between IPF genetic risk and differences in brain structure, for both cortex and white matter. Differences in tissue-specific imaging signatures suggest distinct underlying mechanisms with focal cortical thinning in regions with known high DEPTOR expression, unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function. This study was supported by the NIHR Nottingham Biomedical Research Centre and the UK Medical Research Council.
登录
查看更多内容
影响因子：
30.8
作者：
Fingerlin, Tasha E.;Murphy, Elissa;Zhang, Weiming;Peljto, Anna L.;Brown, Kevin K.;Steele, Mark P.;Loyd, James E.;Cosgrove, Gregory P.;Lynch, David;Groshong, Steve;Collard, Harold R.;Wolters, Paul J.;Bradford, Williamson Z.;Kossen, Karl;Seiwert, Scott D.;du Bois, Roland M.;Garcia, Christine Kim;Devine, Megan S.;Gudmundsson, Gunnar;Isaksson, Helgi J.;Kaminski, Naftali;Zhang, Yingze;Gibson, Kevin F.;Lancaster, Lisa H.;Cogan, Joy D.;Mason, Wendi R.;Maher, Toby M.;Molyneaux, Philip L.;Wells, Athol U.;Moffatt, Miriam F.;Selman, Moises;Pardo, Annie;Kim, Dong Soon;Crapo, James D.;Make, Barry J.;Regan, Elizabeth A.;Walek, Dinesha S.;Daniel, Jerry J.;Kamatani, Yoichiro;Zelenika, Diana;Smith, Keith;McKean, David;Pedersen, Brent S.;Talbert, Janet;Kidd, Raven N.;Markin, Cheryl R.;Beckman, Kenneth B.;Lathrop, Mark;Schwarz, Marvin I.;Schwartz, David A.
通讯作者：
Schwartz, David A.
影响因子：
64.8
作者：
Elliott LT;Sharp K;Alfaro-Almagro F;Shi S;Miller KL;Douaud G;Marchini J;Smith SM
通讯作者：
Smith SM
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4.1
作者：
Bors, Melinda;Tomic, Rade;Whelan, Timothy P. M.
通讯作者：
Whelan, Timothy P. M.