Shared genetic liability and causal effects between major depressive disorder and insomnia.

Deciphering the genetic relationships between major depressive disorder (MDD) and insomnia may facilitate understanding biological mechanisms as well as inform more effective treatment regimens for these conditions. Here, we attempted to investigate mechanisms underlying relationships between MDD and insomnia in the context of shared genetic variations. Shared genetic variation was evaluated by polygenic analysis. In two-sample bidirectional Mendelian randomization (MR) analysis, causal relationships between MDD and insomnia were investigated; the list of shared genomic loci was identified using cross-trait meta-analysis. Putatively causal genes for the two diseases were prioritized by fine-mapping of transcriptome-wide associations. Polygenic analysis identified 15.1 thousand variants as causally influencing MDD, and 10.8 thousand variants as influencing insomnia. Among these variants, 8.5 thousand were shared between the two diseases. MR analysis suggests that genetic liability to MDD and to insomnia have mutual causal effects [MDD on insomnia with odds ratio (OR) = 1.25 and insomnia on MDD with OR = 2.23]. Cross-trait meta-analyses identified 89 genomic loci as being shared between MDD and insomnia, with some of them being prioritized as causal in subsequent fine-mapping of transcriptome-wide association signals. Analysis highlights possible role of endogenous production of nitric oxide in the brain, and the gonadotropic secretion in the pituitary as possibly physiological connectors of MDD and insomnia. Here, we show a substantial shared genetic liability and mutual causal links between MDD and insomnia. Presented findings provide novel insight into phenotypic relationship between these two interconnected conditions.

Gut microbiome and major depressive disorder: insights from two-sample Mendelian randomization.

BACKGROUND: Existing evidence suggests that alterations in the gut microbiome are closely associated with major depressive disorder (MDD). We aimed to reveal the causal relationships between MDD and various microbial taxa in the gut. METHODS: We used the two-sample Mendelian randomization (TSMR) to explore the bidirectional causal effects between gut microbiota and MDD. The genome-wide association studies summary results of gut microbiota were obtained from two large consortia, the MibioGen consortium and the Dutch Microbiome Project, which we analyzed separately. RESULTS: Our TSMR analysis identified 10 gut bacterial taxa that were protective against MDD, including phylum Actinobacteria, order Clostridiales, and family Bifidobacteriaceae (OR: 0.96 ∼ 0.98). Ten taxa were associated with an increased risk of MDD, including phyla Firmicutes and Proteobacteria, class Actinobacteria, and genus Alistipes (OR: 1.01 ∼ 1.09). On the other hand, MDD may decrease the abundance of 12 taxa, including phyla Actinobacteria and Firmicutes, families Bifidobacteriaceae and Defluviitaleaceae (OR: 0.63 ∼ 0.88). MDD may increase the abundance of 8 taxa, including phylum Bacteroidetes, genera Parabacteroides, and Bacteroides (OR: 1.12 ∼ 1.43). CONCLUSIONS: Our study supports that there are mutual causal relationships between certain gut microbiota and the development of MDD suggesting that gut microbiota may be targeted in the treatment of MDD.

Causal Associations between Posttraumatic Stress Disorder and COVID-19.

OBJECTIVE: We aimed to evaluate bidirectional genetic relationships between posttraumatic stress disorder (PTSD) and COVID-19. METHODS: We investigated potential causal associations between PTSD and two COVID-19 conditions (COVID-19 hospitalization and SARS-CoV-2 infection) via Mendelian randomization (MR) analyses. Three genome-wide association study (GWAS) summary datasets were used in the study, including PTSD (N = 174,659), SARS-CoV-2 infection (N = 2,597,856), and COVID-19 hospitalization (N = 2,095,324). We performed a literature-based analysis to uncover molecular pathways connecting PTSD and COVID-19. RESULTS: We found that PTSD exerts a causal effect on SARS-CoV-2 infection (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.00-1.21, p = 0.048) and hospitalized COVID-19 (OR: 1.34, 95% CI: 1.07-1.67, p = 0.001). However, both SARS-CoV-2 infection and hospitalized COVID-19 were not associated with the risk of PTSD. Pathway analysis revealed that several immunity-related genes may link PTSD to COVID-19. CONCLUSIONS: Our study suggests that PTSD was associated with increased risks for COVID-19 susceptibility and severity. Early diagnosis and effective treatment of PTSD in individuals infected with the coronavirus may improve the management of the outcomes of COVID-19.

Genetic mechanisms of COVID-19 and its association with smoking and alcohol consumption.

We aimed to investigate the genetic mechanisms associated with coronavirus disease of 2019 (COVID-19) outcomes in the host and to evaluate the possible associations between smoking and drinking behavior and three COVID-19 outcomes: severe COVID-19, hospitalized COVID-19 and COVID-19 infection. We described the genomic loci and risk genes associated with the COVID-19 outcomes, followed by functional analyses of the risk genes. Then, a summary data-based Mendelian randomization (SMR) analysis, and a transcriptome-wide association study (TWAS) were performed for the severe COVID-19 dataset. A two-sample Mendelian randomization (MR) analysis was used to evaluate the causal associations between various measures of smoking and alcohol consumption and the COVID-19 outcomes. A total of 26 protein-coding genes, enriched in chemokine binding, cytokine binding and senescence-related functions, were associated with either severe COVID-19 or hospitalized COVID-19. The SMR and the TWAS analyses highlighted functional implications of some GWAS hits and identified seven novel genes for severe COVID-19, including CCR5, CCR5AS, IL10RB, TAC4, RMI1 and TNFSF15, some of which are targets of approved or experimental drugs. According to our studies, increasing consumption of cigarettes per day by 1 standard deviation is related to a 2.3-fold increase in susceptibility to severe COVID-19 and a 1.6-fold increase in COVID-19-induced hospitalization. Contrarily, no significant links were found between alcohol consumption or binary smoking status and COVID-19 outcomes. Our study revealed some novel COVID-19 related genes and suggested that genetic liability to smoking may quantitatively contribute to an increased risk for a severe course of COVID-19.

Causal effect of COVID-19 on Alzheimer's disease: A Mendelian randomization study.

It was reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause brain size reduction and cognitive decline. Whether COVID-19 may contribute to the development of Alzheimer's disease (AD) is not known. We conducted genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between AD and three COVID-19 outcomes (SARS-CoV-2 infection, COVID-19 hospitalization, and critical COVID-19) by utilizing genome-wide association study datasets on these traits. A map of COVID-19-driven molecular pathways was constructed to investigate potential mechanisms underlying the COVID-19 and AD connection. Genetic correlation analyses indicated that AD had a significant positive genetic correlation with hospitalized COVID-19 (rg = 0.271). The MR analysis from the inverse-variance-weighted model showed that genetic liabilities to hospitalized COVID-19 (odds ratio: 1.02, 95% confidence interval: 1.01-1.03) and critical COVID-19 (1.01, 1.00-1.02) were associated with an increased risk for AD. However, no causal effect of genetic liability to SARS-CoV-2 infection on AD was detected (1.03, 0.97-1.09). A total of 60 functionally interconnected genes were reported to mediate the COVID-19-AD connection, which showed functional enrichment in immunity-related pathways and tissue enrichment in the lung and brain. Our study suggests that severe COVID-19 may contribute to the development of AD, while suffering a mild case of COVID-19 may not increase the risk for AD. The influence of COVID-19 on AD may be mediated by immunity-related pathways acting predominantly in the lung and brain.

Causal associations and shared genetics between hypertension and COVID-19.

To evaluate the genetic relationship between hypertension and COVID-19 and explore the molecular pathways linking hypertension to COVID-19. We performed genetic correlation and Mendelian randomization (MR) analyses to assess potential associations between hypertension and hospitalized COVID-19. We compared genome-wide association signals to reveal shared genetic variation between hypertension and hospitalized COVID-19. Moreover, hypertension-driven molecular pathways were constructed based on large-scale literature data to understand the influence of hypertension on COVID-19 at the molecular level. Hypertension has a positive genetic correlation with COVID-19 (rg = 0.19). The MR analyses indicate that genetic liability to hypertension confers a causal effect on hospitalized COVID-19 (odds ratio [OR]: 1.05, confidence interval [CI]: 1.00-1.09, p = 0.030). Hypertension and hospitalized COVID-19 have three overlapping loci and share eight protein-coding risk genes, including ABO, CSF2, FUT2, IZUMO1, MAMSTR, NPNT, RASIP1, and WNT3. Molecular pathway analysis suggests that hypertension may promote the development of COVID-19 through the induction of inflammatory pathways. Our study suggests that genetically determined hypertension may increase the risk for severe COVID-19. The shared genetic variation and the connecting molecular pathways may underline causal links between hypertension and COVID-19.

A phenome-wide investigation of risk factors for severe COVID-19.

With the continued spread of COVID-19 globally, it is crucial to identify the potential risk or protective factors associated with COVID-19. Here, we performed genetic correlation analysis and Mendelian randomization analysis to examine genetic relationships between COVID-19 hospitalization and 405 health conditions and lifestyle factors in 456 422 participants from the UK Biobank. The genetic correlation analysis revealed 134 positive and 65 negative correlations, including those with intakes of a variety of dietary components. The MR analysis indicates that a set of body fat-related traits, maternal smoking around birth, basal metabolic rate, lymphocyte count, peripheral enthesopathies and allied syndromes, blood clots in the leg, and arthropathy are causal risk factors for severe COVID-19, while higher education attainment, physical activity, asthma, and never smoking status protect against the illness. Our findings have implications for risk stratification in patients with COVID-19 and the prevention of its severe outcomes.

Shared genetics and causal associations between COVID-19 and multiple sclerosis.

Neuroinflammation caused by COVID-19 negatively impacts brain metabolism and function, while pre-existing brain pathology may contribute to individuals' vulnerability to the adverse consequences of COVID-19. We used summary statistics from genome-wide association studies (GWAS) to perform Mendelian randomization (MR) analyses, thus assessing potential associations between multiple sclerosis (MS) and two COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and COVID-19 hospitalization). Genome-wide risk genes were compared between the GWAS datasets on hospitalized COVID-19 and MS. Literature-based analysis was conducted to construct molecular pathways connecting MS and COVID-19. We found that genetic liability to MS confers a causal effect on hospitalized COVID-19 (odd ratio [OR]: 1.09, 95% confidence interval: 1.03-1.16) but not on SARS-CoV-2 infection (1.03, 1.00-1.05). Genetic liability to hospitalized COVID-19 confers a causal effect on MS (1.15, 1.02-1.30). Hospitalized COVID-19 and MS share five risk genes within two loci, including TNFAIP8, HSD17B4, CDC37, PDE4A, and KEAP1. Pathway analysis identified a panel of immunity-related genes that may mediate the links between MS and COVID-19. Our study suggests that MS was associated with a 9% increased risk for COVID-19 hospitalization, while hospitalized COVID-19 was associated with a 15% increased risk for MS. Immunity-related pathways may underlie the link between MS on COVID-19.

Bidirectional causal associations between type 2 diabetes and COVID-19.

Observational studies have reported high comorbidity between type 2 diabetes (T2D) and severe COVID-19. However, the causality between T2D and COVID-19 has yet to be validated. We performed genetic correlation and Mendelian randomization (MR) analyses to assess genetic relationships and potential causal associations between T2D and three COVID-19 outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, COVID-19 hospitalization, and critical COVID-19). Molecular pathways connecting SARS-CoV-2 and COVID-19 were reconstructed to extract insights into the potential mechanisms underlying the connection. We identified a high genetic overlap between T2D and each COVID-19 outcome (genetic correlations 0.21-0.28). The MR analyses indicated that genetic liability to T2D confers a causal effect on hospitalized COVID-19 (odds ratio 1.08, 95% confidence interval [CI] 1.04-1.12) and critical COVID-19 (1.09, 1.03-1.16), while genetic liability to SARS-CoV-2 infection exerts a causal effect on T2D (1.25, 1.00-1.56). There was suggestive evidence that T2D was associated with an increased risk for SARS-CoV-2 infection (1.02, 1.00-1.03), while critical COVID-19 (1.06, 1.00-1.13) and hospitalized COVID-19 (1.09, 0.99-1.19) were associated with an increased risk for T2D. Pathway analysis identified a panel of immunity-related genes that may mediate the links between T2D and COVID-19 at the molecular level. Our study provides robust support for the bidirectional causal associations between T2D and COVID-19. T2D may contribute to amplifying the severity of COVID-19, while the liability to COVID-19 may increase the risk for T2D.

Penta-SiCN monolayer as a well-balanced performance anode material for Li-ion batteries.

Lithium-ion batteries (LIBs) remain irreplaceable for clean energy storage applications. The intrinsic metallic nature of penta-SiCN ensures its promising application in the electrodes of LIBs. Using first-principles calculations, we evaluate the performance of the intrinsic metallic penta-SiCN monolayer as the anode material for LIBs. Penta-SiCN exhibits a low diffusion energy barrier (0.107 eV) for Li atom migration on Si18C18N18, while the diffusion energy barrier for vacancy migration on Li17Si18C18N18 is only 0.006 eV. Additionally, penta-SiCN possesses a high theoretical capacity of 1485.98 mA h g-1, average open-circuit voltage of 0.97 V, and small volume expansion of 1%. Remarkably, penta-SiCN exhibits robust wettability towards the electrolytes (solvent molecules and metal salts) widely used in commercial LIBs, indicating the excellent compatibility in electrode applications. These intriguing theoretical findings make penta-SiCN a high performance anode material for LIBs.

Causal associations between COVID-19 and childhood mental disorders.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can invade both the peripheral and central nervous systems and impact the function of the brain. Therefore, it is necessary to evaluate the mutual influences between COVID-19 outcomes and childhood mental disorders. METHODS: We examined genetic correlations and potential causalities between three childhood mental disorders and three COVID-19 phenotypes by genetically proxied analyses. The three mental disorders included attention-deficit/hyperactivity disorder (ADHD, N = 292,548), Tourette's syndrome (TS, N = 14,307), and autism spectrum disorder (ASD, N = 46,350). The three COVID-19 traits included SARS-CoV-2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critical COVID-19 (N = 1,086,211). Literature-based analysis was used to build gene-based pathways connecting ADHD and COVID-19. RESULTS: ADHD was positively correlated with the three COVID-19 outcomes (Rg: 0.22 ~ 0.30). Our Mendelian randomization (MR) analyses found that ADHD confers a causal effect on hospitalized COVID-19 (odds ratio (OR): 1.36, 95% confidence interval (CI): 1.10-1.69). TS confers a causal effect on critical COVID-19 (OR: 1.14, 95% CI: 1.04-1.25). Genetic liability to the COVID-19 outcomes may not increase the risk for the childhood mental disorders. Pathway analysis identified several immunity-related genes that may link ADHD to COVID-19, including CRP, OXT, IL6, PON1, AR, TNFSF12, and IL10. CONCLUSIONS: Our study suggests that both ADHD and TS may augment the severity of COVID-19 through immunity-related pathways. However, our results did not support a causal role of COVID-19 in the risk for the childhood mental disorders.

Involvement of the long intergenic non-coding RNA LINC00461 in schizophrenia.

OBJECTIVE: LINC00461 is a highly conserved intergenic non-protein coding RNA that was implicated in schizophrenia at the genome-wide level. We aim to explore potential mechanisms underlying the involvement of LINC00461 in schizophrenia. METHODS: We performed a meta-analysis to investigate the association of LINC00461 rs410216 with schizophrenia, and evaluate the effects of the rs410216 on hippocampal volume and function using the functional magnetic resonance imaging (fMRI) analysis. We utilized the GTEx dataset to profile the expression distribution of LINC00461 across different brain regions, and to investigate the potential impact of the risk SNPs on the expression of LINC00461 and other nearby genes. We compared blood expression levels of LINC00461 between schizophrenia patients and controls. RESULTS: Here we show that single-nucleotide polymorphisms (SNPs) located in regulatory elements spanning the LINC00461 region are significantly associated with schizophrenia (index SNP rs410216, Pmeta = 1.43E-05); subjects carrying the risk allele of rs410216 showed decreased hippocampal volume. However, no significant association of the rs410216 variant with hippocampal activation was observed. Moreover, the expression level of LINC00461 mRNA was significantly lower in first-onset schizophrenia patients, and the risk allele also predicts a lower transcriptional level of LINC00461 in the hippocampus. CONCLUSION: Together, these convergent lines of evidence implicate inadequate LINC00461 expression in the hippocampus in the development of schizophrenia, providing novel insight into the genetic architecture and biological etiology of schizophrenia.

Causal influences of neuroticism on mental health and cardiovascular disease.

We investigated the relationship between neuroticism and 16 mental and 18 physical traits using summary results of genome-wide association studies for these traits. LD score regression was used to investigate genetic correlations between neuroticism and the 34 health outcomes. Mendelian randomization was performed to investigate mutual causal relationships between neuroticism and the 34 health outcomes. Neuroticism genetically correlates with a majority of health-related traits and confers causal effects on 12 mental traits (major depressive disorder (MDD), insomnia, subjective well-being (SWB, negatively), schizophrenia, attention-deficit/hyperactivity disorder, alcohol dependence, loneliness, anorexia nervosa, anxiety disorder, bipolar disorder, obsessive-compulsive disorder, and psychiatric disorders) and two physical diseases (cardiovascular disease and hypertensive disease). Conversely, MDD, SWB, and insomnia have a causal effect on neuroticism. We highlighted key genes contributing to the causal associations between neuroticism and MDD, including RBFOX1, RERE, SOX5, and TCF4, and those contributing to the causal associations between neuroticism and cardiovascular diseases, including MAD1L1, ARNTL, RERE, and SOX6. The present study indicates that genetic variation mediates the causal influences of neuroticism on mental health and cardiovascular diseases.

Identifying common genome-wide risk genes for major psychiatric traits.

Major psychiatric traits are genetically inter-correlated with one another, but it not well known which genes play pleiotropic effects across different traits. We curated and compared genes identified from large-scale genome-wide association studies for seven psychiatric traits, including depression, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety and neuroticism. We then explored biological functions of the top pleiotropic genes. A total of 243 cross-trait genes were identified for the seven traits. Except for autism spectrum disorder, there was significant enrichment of overlapped genes across these psychiatric traits. Chromosome 5q14.3, 11q23.2, and 7p22.3 are the three genomic regions conferring highest pleiotropic effects for these psychiatric traits. The long non-coding gene LINC00461 showed the highest pleiotropic effects on five psychiatric traits. In silico and functional studies with mice support the vital role of LINC00461 in neurodevelopment. In sum, our study provides insights into the shared genetic liability among major psychiatric traits.

Deep vein thrombosis inhibitor may play a therapeutic role in post-stroke patients.

BACKGROUND: Deep vein thrombosis (DVT) is associated with stroke. Here, we hypothesize that genes associated with DVT may also play roles in the development of stroke. METHODS: we firstly conducted large-scale literature based disease-gene relationship data analysis to explore the genes implicated with DVT and stroke. Further, a mega-analysis was conducted for each of these genes that were linked to DVT but not stroke, using 11 independent stroke RNA expression datasets (176 stroke cases and 102 healthy controls). Then, a multiple linear regression (MLR) model was employed to study possible influential factors on the gene expression levels in stroke. After that, a functional pathway analysis was performed to identify the potential biological linkage between stroke and the target genes suggested by mega-analysis. RESULTS: Over 81.10% genes implicated with DVT also suggested an association with stroke. Among the 24 DVT-specific genes, one DVT-inhibiting gene, SP1, presented significantly increased expression in stroke (LFC = 1.34, p-value = 0.0045). Pathway analysis showed that SP1 may play a therapeutic role in post-stroke patients by promoting multiple of stroke-inhibitors. Moreover, geographical region was indicated as an influential factor on the expression levels of SP1 in stroke samples (p-value = 0.037). CONCLUSION: Our results suggested that DVT inhibitor SP1 could be a novel therapeutic target gene for post-stroke treatment. Further study of the potential relations between SP1 and stroke was guaranteed.

Understanding the molecular association between hyperkalemia and lung squamous cell carcinomas.

BACKGROUND: Previous studies indicated a strong association between hyperkalemia and lung squamous cell carcinomas (LSCC). However, the underlying mechanism is not fully understood so far. METHODS: Literature-based data mining was conducted to identify genes, molecule, and cell processes linked to both hyperkalemia and LSCC. Pathway analysis was performed to explore the interactive network, common-target network, and common-regulator network for both disorders. Then, a mega-analysis using 11 independent LSCC RNA expression datasets (358 LSCCs and 278 healthy controls) was performed to test the hypothesis that genes influencing hyperkalemia may also play roles in LSCC. RESULTS: There was a significant overlap between the genes implicated with both diseases (20 genes, p-value = 4.98e-15), which counts for 16% of all hyperkalemia genes (125 genes). Network analysis identified 12 molecules as common targets for hyperkalemia and LSCC, and 19 molecules as common regulators. Moreover, 19 molecules were identified within an interactive network, through which hyperkalemia and LSCC could exert influence on each other. In addition, meta-analysis identified one hyperkalemia promoter, SPP1, as a novel contributor for LSCC (LFC = 2.64; p-value = 2.81e-6). MLR analysis suggests geographical region as an influential factor for the expression levels of SPP1 in LSCC patients (p value = 0.036, 0.054). CONCLUSION: Our results showed that there was a common molecular basis for the pathology of both hyperkalemia and LSCC, and that genes promoting hyperkalemia might also play roles in the development of LSCC. However, this study did not suggest hypercalcemia as a casual factor for LSCC.

Development of two psychological experience questionnaires for screening violence-related mental health disorders of non-psychiatric inpatients.

BACKGROUND: Increased violent events happen in the general hospitals in China and yet non-psychiatric departments do not have tools for violence-tendency screening. METHODS: The current study developed and evaluated two Inpatient Psychological Experience Questionnaires (IPEQs) for the screening of violence-related six mental health disorders: (Inpatient Psychological Experience Questionnaire-1 (IPEQ-1): anxiety, depression and suicidality; Inpatient Psychological Experience Questionnaire-2 (IPEQ-2): paranoid personality disorder, emotionally unstable personality disorder and histrionic personality disorder). Two initial IPEQs (IPEQ-1: 37 items and IPEQ-2: 30 items) were developed and assessed by domain experts. Then 1210 inpatients were recruited and divided into three groups (160, 450 and 600 samples, respectively) for IPEQs item selection and evaluation. During the two-stage item selection, three statistical methods including Pearson's correlation coefficient, exploratory factor analysis and item response theory were applied. For the item evaluation, Cronbach's alpha coefficient, test-retest reliability, criterion-related validity and construct validity of the final questionnaires were measured. RESULTS: Twelve items were selected for each IPEQs. Cronbach's alpha coefficients were 0.91 and 0.78 for IPEQ-1 and IPEQ-2, respectively. Test-retest replication ratios were 0.95 and 0.87 for IPEQ-1 and IPEQ-2, respectively. Correlation coefficients between different disorders and their related-tools scores were [0.51, 0.44] and [0.40, 0.44] for IPEQ-1 and IPEQ-2, respectively and were significant (P < 0.01). Confirmatory factor analysis supported the validity of the final IPEQs (P < 0.05), and the model fit index met the criterion generally. CONCLUSION: The IPEQs developed in this study could be effective and easy-to-use tools for screening inpatients with violence-intendancy in non-psychosomatic departments.

Helicobacter pylori infection associated with an increased risk of colorectal adenomatous polyps in the Chinese population.

BACKGROUND: Gastric Helicobacter pylori (H. pylori) is linked with chronic gastritis, peptic ulcer disease, and gastric malignancy. This study aims to investigate the association of gastric H. pylori with colorectal adenomatous polyps (CAP) in the Chinese population. METHODS: One thousand three hundred seventy five workers of China Petroleum and Chemical Corporation Sinopec Zhenhai Refining & Chemical Branch were recruited. Carbon-13 urea breathes test, and colorectal biopsies were utilized to detect H. pylori and CAP. The correlation between the number and distribution of CAP with H. pylori infection (HPI) was determined. Logistic regression models were applied to calculate the effect of H. pylori on the risk of CAP and pathway studio was used to attribute the cellular processes linking HPI and adenomatous polyps. RESULTS: One hundred Eighty participants were diagnosed as CAP, and 1195 participants were classified as healthy control. The prevalence of HPI in the CAP group was significantly higher than that in the healthy control group (57.8% verse 40.1%) (p<0.001). It was the number not the distribution of CAP corrected with H. pylori status. An increased risk of CAP was found to be associated with H. pylori (OR = 3.237; 95.0% CI 2.184-4.798, p = 0.00) even after multiple parameters adjustment. Pathway studio analysis demonstrated that HPI connected with CAP at multi-level. CONCLUSIONS: HPI is associated with an increased risk of CAP in the Chinese population.