Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk
Mapping brain endophenotypes associated with idiopathic pulmonary fibrosis genetic risk
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绘制与特发性肺纤维化遗传风险相关的大脑内表型
DOI：
10.1101/2022.03.25.22272932
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Mohammadi-Nejad A
中科院分区：
文献类型：
--
作者：
Mohammadi-Nejad A
背景特发性肺纤维化(IPF)是一种严重的肺实质疾病。它具有已知的多基因风险，到目前为止至少涉及基因组的17个区域。越来越多的证据表明，IPF的多发病与神经退行性或情感性疾病有关。然而，到目前为止，还没有研究明确探索IPF、相关的遗传风险特征和特定大脑特征之间的联系。方法我们利用来自超过32,000名参与者的成像和遗传数据，通过英国生物库人口水平资源来探索IPF遗传风险和成像衍生的脑内表型之间的联系。我们在17号染色体(17q21.31)和8号染色体(DEPTOR)上对17个已知的IPF风险变异的存在和1248个多模式成像衍生特征进行了全脑成像-遗传学关联研究，这些特征描述了大脑结构和功能。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脑白质微结构变化与8号染色体上的IPF具有单一的因果变量。事后的初步分析表明，用力肺活量可能部分中介了DEPTOR变量和白质微观结构之间的关联，但不是DEPTOR风险变量和皮质厚度之间的关联。说明我们的结果揭示了IPF遗传风险与大脑结构差异之间的关联，对于皮质和白质来说都是如此。组织特异性成像特征的差异提示了不同的潜在机制，即已知DEPTR高表达区域的局灶性皮质变薄，与肺功能无关，以及与缺氧或神经炎症相一致的更广泛的微结构白质变化，潜在的肺功能调节。基金本研究由NIHR诺丁汉生物医学研究中心和英国医学研究委员会支持。
BackgroundIdiopathic 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.MethodsWe 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.FindingsWe 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 theDEPTORvariant and white matter microstructure, but not between theDEPTORrisk variant and cortical thickness.InterpretationOur 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 highDEPTORexpression, unrelated to lung function, and more widespread microstructural white matter changes consistent with hypoxia or neuroinflammation with potential mediation by lung function.FundingThis study was supported by the NIHR Nottingham Biomedical Research Centre and the UK Medical Research Council.
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影响因子：
76.2
作者：
Noth, Imre;Zhang, Yingze;Ma, Shwu-Fan;Flores, Carlos;Barber, Mathew;Huang, Yong;Broderick, Steven M.;Wade, Michael S.;Hysi, Pirro;Scuirba, Joseph;Richards, Thomas J.;Juan-Guardela, Brenda M.;Vij, Rekha;Han, MeiLan K.;Martinez, Fernando J.;Kossen, Karl;Seiwert, Scott D.;Christie, Jason D.;Nicolae, Dan;Kaminski, Naftali;Garcia, Joe G. N.
通讯作者：
Garcia, Joe G. N.
影响因子：
15.1
作者：
Chen Y;Dang M;Zhang Z
通讯作者：
Zhang Z
DOI：
--
发表时间：
2010
期刊：
影响因子：
--
作者：
McCormack FX;Sullivan EJ;Inoue Y.
通讯作者：
Inoue Y.
影响因子：
30.8
作者：
Boettger, Linda M.;Handsaker, Robert E.;Zody, Michael C.;McCarroll, Steven A.
通讯作者：
McCarroll, Steven A.
未成熟雪貂慢性缺氧后组织病理学与弥散张量成像的相关性
影响因子：
3.6
作者：
J. Tao;A. Barnette;J. Griffith;J. Neil;T. Inder
通讯作者：
T. Inder