Linking genomic and proteomic signatures to brain amyloid burden: insights from GR@ACE/DEGESCO

IF 3.9 4区 生物学 Q1 GENETICS & HEREDITY
Raquel Puerta, Itziar de Rojas, Pablo García-González, Clàudia Olivé, Oscar Sotolongo-Grau, Ainhoa García-Sánchez, Fernando García-Gutiérrez, Laura Montrreal, Juan Pablo Tartari, Ángela Sanabria, Vanesa Pytel, Carmen Lage, Inés Quintela, Nuria Aguilera, Eloy Rodriguez-Rodriguez, Emilio Alarcón-Martín, Adelina Orellana, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo López de Munain, Jose María García-Alberca, Jose Luís Royo, María J. Bullido, Victoria Álvarez, Luis Miguel Real, Arturo Corbatón Anchuelo, Dulcenombre Gómez-Garre, María Teresa Martínez Larrad, Emilio Franco-Macías, Pablo Mir, Miguel Medina, Raquel Sánchez-Valle, Oriol Dols-Icardo, María Eugenia Sáez, Ángel Carracedo, Lluís Tárraga, Montse Alegret, Sergi Valero, Marta Marquié, Mercè Boada, Pascual Sánchez Juan, Jose Enrique Cavazos, Alfredo Cabrera-Socorro, Amanda Cano, Agustín Ruiz, for the Alzheimer’s Disease Neuroimaging Initiative
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引用次数: 0

Abstract

Alzheimer’s disease (AD) is a complex disease with a strong genetic component, yet many genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may provide insights into the underlying biology of the disease. We performed a meta-GWAS of CSF Aβ42 and PET measures combining six independent cohorts (n = 2,076). Given the opposite beta direction of Aβ phenotypes in CSF and PET measures, only genetic signals showing opposite directions were considered for analysis (n = 376,599). We explored the amyloidosis signature in the CSF proteome using SOMAscan proteomics (ACE cohort, n = 1,008), connected it with GWAS loci modulating amyloidosis and performed an enrichment analysis of overlapping hits. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n = 13,409) and PET (n = 13,116). After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and annotated nine suggestive hits. We replicated the APOE loci using the large CSF-PET meta-GWAS, identifying multiple AD-associated genes including the novel GADL1 locus. Additionally, we found 1,387 FDR-significant SOMAscan proteins associated with CSF Aβ42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was minimal (n = 35). The enrichment analysis revealed mechanisms connecting amyloidosis with the plasma membrane’s anchored component, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Combining CSF and PET amyloid GWAS with CSF proteome analyses may effectively elucidate causative molecular mechanisms behind amyloid mobilization and AD physiopathology.

将基因组和蛋白质组学特征与脑淀粉样蛋白负担联系起来:来自GR@ACE/DEGESCO的见解
阿尔茨海默病(AD)是一种复杂的疾病,具有很强的遗传成分,但许多遗传风险因素尚不清楚。我们结合脑脊液(CSF)和正电子发射断层扫描(PET)测量淀粉样蛋白内表型的全基因组关联研究(GWAS)作为淀粉样蛋白病理学的替代品,这可能为该疾病的潜在生物学提供见解。我们对6个独立队列(n = 2076)进行了CSF a- β42和PET测量的meta-GWAS。鉴于CSF和PET测量中Aβ表型的相反β方向,仅考虑显示相反方向的遗传信号进行分析(n = 376,599)。我们使用SOMAscan蛋白质组学(ACE队列,n = 1008)探索脑脊液蛋白质组中的淀粉样变特征,将其与调节淀粉样变的GWAS位点联系起来,并对重叠点进行富集分析。最后,我们将我们的结果与一项大型荟萃分析进行了比较,该荟萃分析使用了CSF (n = 13,409)和PET (n = 13,116)的公开数据集。筛选meta-GWAS后,我们观察到rs429358-APOE位点具有全基因组意义,并注释了9个提示点。我们使用大型CSF-PET meta-GWAS复制APOE位点,鉴定了多个ad相关基因,包括新的GADL1位点。此外,我们发现1,387个fdr显著的SOMAscan蛋白与CSF a - β42水平相关。GWAS基因座与淀粉样蛋白负荷相关蛋白之间的重叠极少(n = 35)。富集分析揭示了淀粉样变性与质膜锚定成分、突触生理和精神障碍之间的联系机制,这在大型CSF-PET荟萃分析中得到了重复。将脑脊液和PET淀粉样蛋白GWAS与脑脊液蛋白质组分析相结合,可以有效地阐明淀粉样蛋白动员和AD生理病理背后的致病分子机制。
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来源期刊
CiteScore
3.50
自引率
3.40%
发文量
92
审稿时长
2 months
期刊介绍: Functional & Integrative Genomics is devoted to large-scale studies of genomes and their functions, including systems analyses of biological processes. The journal will provide the research community an integrated platform where researchers can share, review and discuss their findings on important biological questions that will ultimately enable us to answer the fundamental question: How do genomes work?
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