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CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

ABSTRACT: The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16?795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and A? levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

SUBMITTER: Zhang DF

PROVIDER: S-EPMC4748428 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

Zhang Deng-Feng DF Li Jin J Wu Huan H Cui Yue Y Bi Rui R Zhou He-Jiang HJ Wang Hui-Zhen HZ Zhang Chen C Wang Dong D Kong Qing-Peng QP Li Tao T Fang Yiru Y Jiang Tianzi T Yao Yong-Gang YG

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20150805 4

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endo ...[more]

PMID: 26243271

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Project description:Rationale: To identify functionally relevant common genetic risk variants associated with idiopathic pulmonary fibrosis (IPF), we performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals as well as mediation analysis. Methods: Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased control (188 RNA and 202 DNA samples). Transcriptome and methylome datasets were normalized for unknown batch effects using Probabilistic Estimation of Expression Residuals (PEER). eQTL, cell type-interaction eQTL, and mQTL analyses were performed in FastQTL and co-localization analysis in eCAVIAR separately for cases and controls. Benjamini-Hochberg false discovery rate was used for adjustment for multiple comparisons. Results: After appropriate adjustment, we identified 4,745 genes with significant eQTLs in controls and 6,047 in cases (FDR-adjusted p<0.05). Focusing on genetic variants within 10 primary IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (FDR-adjusted p<0.05). Among these signals, we identified association of rs35705950 with expression of MUC5B (Chr11 locus) and rs2076295 with expression of DSP (Chr6 locus) in both cases and controls. To address cell specificity, we performed cell type-interaction eQTL analysis and identified an association of rs2076295 with expression of DSP in smooth muscle cells. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. eCAVIAR demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295) in both cases and controls. Mediation analysis demonstrated partial mediation of the effect of common variants in MUC5B and DSP loci on disease risk though MUC5B and DSP gene expression. Functional validation of the mQTL in MUC5B demonstrates that the CpG is within a putative internal repressor element that interacts through a 3D loop with the enhancer containing the rs35705950 genetic variant. Conclusions: Using lung eQTL/mQTL, co-localization, and mediation analyses, we have established the functional validation of the common IPF genetic risk variants for MUC5B (rs35705950) and DSP (rs2076295). These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.

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Dataset Information

CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

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CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

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