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Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain.

ABSTRACT: BACKGROUND:The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (nmax?=?1601), classical AD neuropathology (nmax?=?985), or microglial density (nmax?=?184). METHODS:Longitudinal cognitive decline, postmortem amyloid and tau neuropathology, microglial density, and gene module expression from bulk brain tissue were all measured in participants from two large cohorts (the Rush Religious Orders Study and Memory and Aging Project; ROS/MAP) of elderly subjects (mean age at entry 78 +/-?8.7 years). We analyzed data primarily using robust regression methods. Neuropathologists were blind to clinical data. RESULTS:The AD genetic risk scores, including and excluding APOE effects, were strongly associated with cognitive decline in all domains (min Puncor?=?3.2?×?10-?29). Multiple sclerosis (MS), Parkinson's disease, and schizophrenia risk did not influence cognitive decline in older age, but the rheumatoid arthritis (RA) risk score alone was significantly associated with microglial density after correction (t146?=?-?3.88, Puncor?=?1.6?×?10-?4). Post-hoc tests found significant effects of the RA genetic risk score in multiple regions and stages of microglial activation (min Puncor?=?1.5?×?10-?6). However, these associations were driven by only one or two variants, rather than cumulative polygenicity. Further, individual MS (Pone-sided?

SUBMITTER: Felsky D

PROVIDER: S-EPMC6057096 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain.

Felsky Daniel D Patrick Ellis E Schneider Julie A JA Mostafavi Sara S Gaiteri Chris C Patsopoulos Nikolaos N Bennett David A DA De Jager Philip L PL

Molecular neurodegeneration 20180724 1

<h4>Background</h4>The role of the innate immune system in Alzheimer's disease (AD) and neurodegenerative disease susceptibility has recently been highlighted in genetic studies. However, we do not know whether risk for inflammatory disease predisposes unaffected individuals to late-life cognitive deficits or AD-related neuropathology. We investigated whether genetic risk scores for seven immune diseases and central nervous system traits were related to cognitive decline (n<sub>max</sub> = 1601) ...[more]

PMID: 30041668

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Project description:BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p?=?0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p?=?0.066) and UC (OR 1.18 [0.97-1.43], p?=?0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p?=?6.8×10(-5); OR?=?2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p?=?0.029; OR?=?0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor ROR? which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants.

Dataset Information

Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain.

Publications

Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain.

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