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Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases.

ABSTRACT: The human lifespan is a heritable trait, which is intricately linked to the development of disorders. Here, we show that genetic associations for the parental lifespan are enriched in open chromatin of blood cells. By using blood expression quantitative trait loci (eQTL) derived from 31,684 samples, we identified for the lifespan 125 cis- and 559 trans-regulated expressed genes (eGenes) enriched in adaptive and innate responses. Analysis of blood single-cell expression data showed that eGenes were enriched in dendritic cells (DCs) and the modelling of cell ligand-receptor interactions predicted crosstalk between DCs and a cluster of monocytes with a signature of cytotoxicity. In two-sample Mendelian randomization (MR), we identified 16 blood cis-eGenes causally associated with the lifespan. In MR, the majority of cis-eGene-disorder association pairs had concordant effects with the lifespan. The present work underlined that the lifespan is linked with the immune response and identifies eGenes associated with the lifespan and disorders.

SUBMITTER: Chignon A

PROVIDER: S-EPMC7195437 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases.

Chignon Arnaud A Bon-Baret Valentin V Boulanger Marie-Chloé MC Li Zhonglin Z Argaud Deborah D Bossé Yohan Y Thériault Sébastien S Arsenault Benoit J BJ Mathieu Patrick P

Communications biology 20200501 1

The human lifespan is a heritable trait, which is intricately linked to the development of disorders. Here, we show that genetic associations for the parental lifespan are enriched in open chromatin of blood cells. By using blood expression quantitative trait loci (eQTL) derived from 31,684 samples, we identified for the lifespan 125 cis- and 559 trans-regulated expressed genes (eGenes) enriched in adaptive and innate responses. Analysis of blood single-cell expression data showed that eGenes we ...[more]

PMID: 32358504

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Project description:BackgroundAccumulating evidence has demonstrated that an association between chronic pain and autoimmune diseases (AIDs). Nevertheless, it is unclear whether these associations refer to a causal relationship. We used a two-sample Mendelian randomization (MR) method to determine the causal relationship between chronic pain and AIDs.MethodsWe assessed genome-wide association study (GWAS) summary statistics for chronic pain [multisite chronic pain (MCP) and chronic widespread pain (CWP)], and eight common AIDs, namely, amyotrophic lateral sclerosis (ALS), celiac disease (CeD), inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), type 1 diabetes (T1D) and psoriasis. Summary statistics data were from publicly available and relatively large-scale GWAS meta-analyses to date. The two-sample MR analyses were first performed to identify the causal effect of chronic pain on AIDs. The two-step MR and multivariable MR were used to determine if mediators (BMI and smoking) causally mediated any connection and to estimate the proportion of the association mediated by these factors combined.ResultsWith the utilization of MR analysis, multisite chronic pain was associated with a higher risk of MS [odds ratio (OR) = 1.59, 95% confidence interval (CI) = 1.01-2.49, P = 0.044] and RA (OR = 1.72, 95% CI = 1.06-2.77, P = 0.028). However, multisite chronic pain had no significant effect on ALS (OR = 1.26, 95% CI = 0.92-1.71, P = 0.150), CeD (OR = 0.24, 95% CI = 0.02-3.64, P = 0.303), IBD (OR = 0.46, 95% CI = 0.09-2.27, P = 0.338), SLE (OR = 1.78, 95% CI = 0.82-3.88, P = 0.144), T1D (OR = 1.15, 95% CI = 0.65-2.02, P = 0.627) or Psoriasis (OR = 1.59, 95% CI = 0.22-11.26, P = 0.644). We also found positive causal effects of MCP on BMI and causal effects of BMI on MS and RA. Moreover, there were no causal connections between genetically predicted chronic widespread pain and the risk of most types of AIDs disease.ConclusionOur MR analysis implied a causal relationship between MCP and MS/RA, and the effect of MCP on MS and RA may be partially mediated by BMI.

Project description:BACKGROUND:High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS:We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ?750?000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS:A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm?Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm?Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm?Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm?Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS:Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.

Project description:BACKGROUND:High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach. METHODS:For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays. RESULTS:Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 ?mol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 ?mol/L, Z?=?-5.29, P?<?0.01) and in healthy controls (median: 18.32 vs. 10.00 ?mol/L, Z?=?-8.76, P?<?0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 ?mol/L, Z?=?-1.32, P?=?0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, ??=?14.29, P?<?0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 ?mol/L, ??=?34.06, P?<?0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, ??=?21.75, P?<?0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, ??=?2.97, P?=?0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, ??=?11.47, P?<?0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, ??=?17.66, P?<?0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P?<?0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (??=?0.76, P?=?0.02), systolic blood pressure (??=?0.26, P?=?0.02), diastolic blood pressure (??=?0.20, P?=?0.01), and pathologic T lesion (??=?0.01, P?=?0.01) in IgAN. CONCLUSIONS:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.

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Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases.

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Single-cell expression and Mendelian randomization analyses identify blood genes associated with lifespan and chronic diseases.

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