No evidence of association between either Modic change or disc degeneration and five circulating inflammatory proteins.

Introduction: Intervertebral disc degeneration and Modic change are the main spinal structural changes associated with chronic low back pain (LBP). Both conditions are thought to manifest local inflammation and if inflammatory proteins translocate to the blood circulation could be detected systemically. The work here assesses whether the presence of disc degeneration is associated with detectable blood level changes of five inflammatory markers and whether chronic LBP is associated with these changes. Materials and Methods: Two hundred and forty TwinsUK cohort participants with both MRI disc degeneration grade and Modic change extent, and IL-6, IL-8, IL-8 TNF, and CX3CL1 protein blood concentration measurements were included in this work. Linear mixed effects models were used to test the association of blood cytokine concentration with disc degeneration score and Modic change volumetric score. Association of chronic LBP status from questionnaires with disc degeneration, Modic change, and cytokine blood concentration was also tested. Results: No statistically significant association between disc degeneration or Modic change with cytokine blood concentration was found. Instead, regression analysis pointed strong association between cytokine blood concentration with body mass index for IL-6 and with age for IL-6 and TNF. Mild association was found between IL-8 blood concentration and body mass index. Additionally, LBP status was associated with Modic change volumetric score but not associated with any cytokine concentration. Conclusions: We found no evidence that Modic change and disc degeneration are able to produce changes in tested blood cytokine concentration. However, age and body mass index have strong influence on cytokine concentration and both are associated with the conditions studied which may confound associations found in the literature. It is then unlikely that cytokines produced in the disc or vertebral bone marrow induce chronic LBP.

Treatment response in rheumatoid arthritis is predicted by the microbiome: a large observational study in UK DMARD-naïve patients.

OBJECTIVES: Disease-modifying antirheumatic drugs (DMARDs) are first line treatment in rheumatoid arthritis (RA). Treatment response to DMARDs is patient-specific, dose efficacy is difficult to predict and long-term results variable. The gut microbiota are known to play a pivotal role in prodromal and early-disease RA, manifested by Prevotella spp. enrichment. The clinical response to therapy may be mediated by microbiota, and large-scale studies assessing the microbiome are few. This study assessed whether microbiome signals were associated with, and predictive of, patient response to DMARD-treatment. Accurate early identification of those who will respond poorly to DMARD therapy would allow selection of alternative treatment (e.g. biologic therapy), and potentially improve patient outcome. METHODS: A multicentre, longitudinal, observational study of stool- and saliva microbiome was performed in DMARD-naïve, newly diagnosed RA patients during introduction of DMARD treatment. Clinical data and samples were collected at baseline (n = 144) in DMARD-naïve patients and at six weeks (n = 117) and 12 weeks (n = 95) into DMARD-therapy. Samples collected (n = 365 stool, n = 365 saliva) underwent shotgun sequencing. Disease activity measures were collected at each timepoint and minimal clinically important improvement determined. RESULTS: In total, 26 stool microbes were found to decrease in those manifesting a minimal clinically important improvement. Prevotella spp. and Streptococcus spp. were the predominant taxa to decline following six weeks and 12 weeks of DMARDs, respectively. Furthermore, baseline microbiota of DMARD-naïve patients were indicative of future response. CONCLUSION: DMARDs appear to restore a perturbed microbiome to a eubiotic state. Moreover, microbiome status can be used to predict likelihood of patient response to DMARD.

Multi-Trait Exome-Wide Association Study of Back Pain-Related Phenotypes.

Back pain (BP) is a major contributor to disability worldwide, with heritability estimated at 40-60%. However, less than half of the heritability is explained by common genetic variants identified by genome-wide association studies. More powerful methods and rare and ultra-rare variant analysis may offer additional insight. This study utilized exome sequencing data from the UK Biobank to perform a multi-trait gene-based association analysis of three BP-related phenotypes: chronic back pain, dorsalgia, and intervertebral disc disorder. We identified the SLC13A1 gene as a contributor to chronic back pain via loss-of-function (LoF) and missense variants. This gene has been previously detected in two studies. A multi-trait approach uncovered the novel FSCN3 gene and its impact on back pain through LoF variants. This gene deserves attention because it is only the second gene shown to have an effect on back pain due to LoF variants and represents a promising drug target for back pain therapy.

Repurposing Antihypertensive and Statin Medications for Spinal Pain: A Mendelian Randomization Study.

STUDY DESIGN: Mendelian randomization (MR) study. OBJECTIVE: To examine whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal pain (back or neck pain). SUMMARY OF BACKGROUND DATA: Observational studies and a recent MR study have found associations between elevated blood pressure and a greater risk of back pain. Observational studies have found associations between hyperlipidemia and statin use and greater risk of back pain. No prior MR studies have examined the effects of antihypertensives or statins on spinal pain. MATERIALS AND METHODS: This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies (GWAS). Sample sizes in exposure GWASs were n=757,601 (systolic blood pressure) and n=173,082 (low-density lipoprotein cholesterol), and n=1,028,947 for the outcome GWAS of spinal pain defined as health care seeking for any spinal pain-related diagnosis. Genes and cis-acting variants were identified as proxies for the drug targets of interest. MR analyses used inverse-variance weighted meta-analysis. The threshold for statistical significance after correction for multiple testing was P <0.0125. RESULTS: No statistically significant associations of these medications with spinal pain were found. However, findings were suggestive of a protective effect of beta-blockers on spinal pain risk (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72-0.98; P =0.03), and calcium channel blockers on greater spinal pain risk (OR 1.12, 95% CI 1.02-1.24; P =0.02). CONCLUSIONS: A protective effect of beta-blockers on spinal pain was suggested in the current study, consistent with findings from observational studies of various other pain phenotypes. The detrimental effect of calcium channel blockers on spinal pain suggested in the current study must be interpreted in the context of conflicting directions of effect on nonspinal pain phenotypes in other observational studies.This Mendelian randomization study examined whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal.This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies ranging size from 173,082 to 1,028,947 adults.While no statistically significant associations were found, a protective effect of beta-blockers on spinal pain was suggested (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72 to 0.98; p= 0.03), as was a detrimental effect of calcium channel blockers on spinal pain (OR 1.12, 95% CI 1.02 to 1.24; p= 0.02).

Apoptosis Genes as a Key to Identification of Inverse Comorbidity of Huntington's Disease and Cancer.

Cancer and neurodegenerative disorders present overwhelming challenges for healthcare worldwide. Epidemiological studies showed a decrease in cancer rates in patients with neurodegenerative disorders, including the Huntington disease (HD). Apoptosis is one of the most important processes for both cancer and neurodegeneration. We suggest that genes closely connected with apoptosis and associated with HD may affect carcinogenesis. We applied reconstruction and analysis of gene networks associated with HD and apoptosis and identified potentially important genes for inverse comorbidity of cancer and HD. The top 10 high-priority candidate genes included APOE, PSEN1, INS, IL6, SQSTM1, SP1, HTT, LEP, HSPA4, and BDNF. Functional analysis of these genes was carried out using gene ontology and KEGG pathways. By exploring genome-wide association study results, we identified genes associated with neurodegenerative and oncological disorders, as well as their endophenotypes and risk factors. We used publicly available datasets of HD and breast and prostate cancers to analyze the expression of the identified genes. Functional modules of these genes were characterized according to disease-specific tissues. This integrative approach revealed that these genes predominantly exert similar functions in different tissues. Apoptosis along with lipid metabolism dysregulation and cell homeostasis maintenance in the response to environmental stimulus and drugs are likely key processes in inverse comorbidity of cancer in patients with HD. Overall, the identified genes represent the promising targets for studying molecular relations of cancer and HD.

Bidirectional Mendelian Randomization Study of Personality Traits Reveals a Positive Feedback Loop Between Neuroticism and Back Pain.

We conducted a bidirectional Mendelian randomization study to examine the causal effects of six personality traits (anxiety, neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) on back pain associated with health care use and the causal effect of back pain on the same risk factors. Genetic instruments for the personality traits and back pain were obtained from the largest published genome-wide association studies conducted in individuals of European ancestry. We used inverse weighted variance meta-analysis and Causal Analysis Using Summary Effect for primary analyses and sensitivity analyses to examine evidence for causal associations. We interpreted exposure-outcome associations as being consistent with a causal relationship if results of at least one primary analysis were statistically significant after accounting for multiple statistical testing (P-value < .0042), and the direction and magnitude of effect estimates were concordant between primary and sensitivity analyses. We found evidence for statistically significant bidirectional causal associations between neuroticism and back pain, with odds ratio 1.51 (95% confidence interval 1.37; 1.67) of back pain per neuroticism sum score standard deviation, P-value = 7.80e-16; and beta = .12, se = .04 of neuroticism sum score standard deviation per log odds of back pain, P-value = 2.48e-03. Other relationships did not meet our predefined criteria for causal association. PERSPECTIVE: The significant positive feedback loop between neuroticism and back pain highlights the importance of considering neuroticism in the management of patients with back pain.

Association between HSPA8 Gene Variants and Ischemic Stroke: A Pilot Study Providing Additional Evidence for the Role of Heat Shock Proteins in Disease Pathogenesis.

HSPA8 is involved in many stroke-associated cellular processes, playing a pivotal role in the protein quality control system. Here we report the results of the pilot study aimed at determining whether HSPA8 SNPs are linked to the risk of ischemic stroke (IS). DNA samples from 2139 Russians (888 IS patients and 1251 healthy controls) were genotyped for tagSNPs (rs1461496, rs10892958, and rs1136141) in the HSPA8 gene using probe-based PCR. SNP rs10892958 of HSPA8 was associated with an increased risk (risk allele G) of IS in smokers (OR = 1.37; 95% CI = 1.07-1.77; p = 0.01) and patients with low fruit and vegetable consumption (OR = 1.36; 95% CI = 1.14-1.63; p = 0.002). SNP rs1136141 of HSPA8 was also associated with an increased risk of IS (risk allele A) exclusively in smokers (OR = 1.68; 95% CI = 1.23-2.28; p = 0.0007) and in patients with a low fruit and vegetable intake (OR = 1.29; 95% CI = 1.05-1.60; p = 0.04). Sex-stratified analysis revealed an association of rs10892958 HSPA8 with an increased risk of IS in males (risk allele G; OR = 1.30; 95% CI = 1.05-1.61; p = 0.01). Thus, SNPs rs10892958 and rs1136141 in the HSPA8 gene represent novel genetic markers of IS.

Development and Replication of a Genome-Wide Polygenic Risk Score for Chronic Back Pain.

Chronic back pain (CBP) is a complex heritable trait and a major cause of disability worldwide. We developed and validated a genome-wide polygenic risk score (PRS) for CBP using a large-scale GWAS based on UK Biobank participants of European ancestry (N = 265,000). The PRS showed poor overall predictive ability (AUC = 0.56 and OR = 1.24 per SD, 95% CI: 1.22-1.26), but individuals from the 99th percentile of PRS distribution had a nearly two-fold increased risk of CBP (OR = 1.82, 95% CI: 1.60-2.06). We validated the PRS on an independent TwinsUK sample, obtaining a similar magnitude of effect. The PRS was significantly associated with various ICD-10 and OPCS-4 diagnostic codes, including chronic ischemic heart disease (OR = 1.1, p-value = 4.8 × 10-15), obesity, metabolism-related traits, spine disorders, disc degeneration, and arthritis-related disorders. PRS and environment interaction analysis with twelve known CBP risk factors revealed no significant results, suggesting that the magnitude of G × E interactions with studied factors is small. The limited predictive ability of the PRS that we developed is likely explained by the complexity, heterogeneity, and polygenicity of CBP, for which sample sizes of a few hundred thousand are insufficient to estimate small genetic effects robustly.

Polymorphism of SERF2, the gene encoding a heat-resistant obscure (Hero) protein with chaperone activity, is a novel link in ischemic stroke.

Background: Ischemic stroke (IS) is one of the most serious cardiovascular events associated with high risk of death or disability. The growing body of evidence highlights molecular chaperones as especially important players in the pathogenesis of the disease. Since six small proteins called "Hero" have been recently identified as a novel class of chaperones we aimed to evaluate whether SNP rs4644832 in SERF2 gene encoding the member of Hero-proteins, is associated with the risk of IS. Methods: A total of 1929 unrelated Russians (861 patients with IS and 1068 healthy individuals) from Central Russia were recruited into the study. Genotyping was done using a probe-based PCR approach. Statistical analysis was carried out in the whole group and stratified by age, gender and smoking status. Results: Analysis of the link between rs4644832 SERF2 and IS showed that G allele is the risk factor of IS only in females (OR=1.29, 95%CI 1.02-1.64, Padj=0.035). In addition, the analysis of associations of rs4644832 SERF2 and IS depending on the smoking status revealed that this genetic variant is associated with an increased risk of IS exclusively in non-smoking individuals (OR=1.26, 95%CI 1.01-1.56, P = 0.041). Discussion: Sex- and smoking interactions between rs4644832 polymorphism and IS may be related to the impact of tobacco components metabolism and sex hormones on SERF2 expression. Conclusion: The present study reveals the novel genetic association between rs4644832 polymorphism and the risk of IS suggesting that SERF2, the part of the protein quality control system, contributes to the pathogenesis of the disease.

Evidence of causal effects of blood pressure on back pain and back pain on type II diabetes provided by a bidirectional Mendelian randomization study.

BACKGROUND CONTEXT: Cardiovascular risk factors (hypertension, dyslipidemia, and type II diabetes) have been proposed as risk factors for back pain. However, few longitudinal studies have found significant associations between cardiovascular risk factors and back pain, and these may be explained by confounding or reverse causation. PURPOSE: To examine potential causal effects of cardiovascular risk factors on back pain, and vice versa. STUDY DESIGN: Bidirectional Mendelian randomization (MR) study. PATIENT SAMPLES: Genome-wide association studies (GWAS) with sample sizes between 173,082 and 1,028,947 participants. OUTCOME MEASURES: Outcomes included (1) back pain associated with health care use (BP-HC) in the forward MR; and (2) seven cardiovascular phenotypes in the reverse MR, including 2 measurements used for the evaluation of hypertension (diastolic blood pressure and systolic blood pressure), 4 phenotypes related to dyslipidemia (LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides), and type II diabetes. METHODS: We used summary statistics from large, publicly available GWAS for BP-HC and the 7 cardiovascular phenotypes to obtain genetic instrumental variables. We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis, Causal Analysis Using Summary Effect (CAUSE), and sensitivity analyses. RESULTS: In forward MR analyses of seven cardiovascular phenotypes, diastolic blood pressure was associated with BP-HC across all analyses (IVW estimate: OR = 1.10 per 10.5 mm Hg increase [1.04-1.17], p-value = .001), and significant associations of systolic blood pressure with BP-HC were also found (IVW estimate: OR = 1.09 per 19.3 mm Hg increase [1.04-1.15], p-value = .0006). In reverse MR analyses, only type II diabetes was associated with BP-HC across all analyses (IVW estimate: OR = 1.40 [1.13-1.73], p-value = .002). CONCLUSIONS: These findings from analyses of large, population-based samples indicate that higher blood pressure increases the risk of BP-HC, and BP-HC itself increases the risk of type II diabetes.

Genotype-by-environment interactions in chronic back pain.

BACKGROUND CONTEXT: Chronic back pain (CBP) is a common debilitating condition with substantial societal impact. While understanding genotype-by-environment (GxE) interactions may be crucial to achieving the goals of personalized medicine, there are few large-scale studies investigating this topic for CBP. None of them systematically explore multiple CBP risk factors. PURPOSE: To estimate the extent to which genetic effects on CBP are modified by known demographic and clinical risk factors. RESEARCH DESIGN: Case-control study, genome-wide GxE interaction study. PATIENT SAMPLE: Data on up to 331,610 unrelated participants (57,881 CBP cases and 273,729 controls) from the UK Biobank cohort were used. UK Biobank is a prospective cohort with collected deep genetic and phenotypic data on approximately 500,000 individuals across the UK. OUTCOME MEASURES: Self-reported chronic back pain. METHODS: We applied a whole-genome approach to estimate the proportion of phenotypic variance explained by interactions between genotype and 12 known risk factors. We also analyzed if effects of common single-nucleotide polymorphisms on CBP are changed in presence of known risk factors. RESULTS: The results indicate a modest, if any, modification of genetic effects by examined risk factors in CBP. Our estimates suggest that detecting such weak effects would require a sample size of millions of individuals. CONCLUSIONS: The GxE interactions with examined common risk factors for CBP are either weak or absent. Interactions of such magnitude are unlikely to have the potential to inform and influence treatment strategies. Risk estimation models may use common genetic variation and the considered risk factors as independent predictors, without accounting for GxE.

Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19.

OBJECTIVE AND DESIGN: Fatigue is a prominent symptom in the general population and may follow viral infection, including SARS-CoV2 infection which causes COVID-19. Chronic fatigue lasting more than three months is the major symptom of the post-COVID syndrome (known colloquially as long-COVID). The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of long-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual prior to COVID-19. SUBJECTS AND METHODS: We analyzed pre-pandemic plasma levels of IL-6, which plays a key role in persistent fatigue, in N = 1274 community dwelling adults from TwinsUK. Subsequent COVID-19-positive and -negative participants were categorized based on SARS-CoV-2 antigen and antibody testing. Chronic fatigue was assessed using the Chalder Fatigue Scale. RESULTS: COVID-19-positive participants exhibited mild disease. Chronic fatigue was a prevalent symptom among this population and significantly higher in positive vs. negative participants (17% vs 11%, respectively; p = 0.001). The qualitative nature of chronic fatigue as determined by individual questionnaire responses was similar in positive and negative participants. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in negative, but not positive individuals. Raised BMI was associated with chronic fatigue in positive participants. CONCLUSIONS: Pre-existing increased IL-6 levels may contribute to chronic fatigue symptoms, but there was no increased risk in individuals with mild COVID-19 compared with uninfected individuals. Elevated BMI also increased the risk of chronic fatigue in mild COVID-19, consistent with previous reports.

The Role of Glutamatergic Gene Polymorphisms in the Clinical Phenotypes of Schizophrenia.

BACKGROUND: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity-both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. METHODS: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. RESULTS: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). CONCLUSIONS: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated.

Ficolin-3 and MASP-2 gene variants in Siberian arctic populations: Summarized evidence of selective pressure for the high frequency of lectin complement pathway deficiency.

Herewith, we provide novel original data about the prevalence of FCN3 rs532781899 and MASP2 rs72550870 variants among the newborns of aboriginal Siberian Arctic populations (Nenets and Dolgan-Nganasans) and Russians of East Siberia. This novel data has been analysed along with the genetic data about other proteins of the lectin pathway of the complement system (mannose-binding lectin and ficolin-2) obtained earlier. A total of 926 specimens of dried blood spots of the newborns were genotyped. The newborns represented four populations: Nenets, Dolgan-Nganasans, Mixed aboriginal population, and Russians (Caucasians) to study the prevalence of single nucleotide polymorphisms of FCN3 rs532781899 and MASP2 rs72550870. The prevalence of the deletion allele of the rs532781899 variant in the FCN3 gene associated with the decreased production of ficolin-3 was found to be increased in Russians compared to the Nenets aboriginal populations (P = .002). The prevalence of the rs72550870*G allele in the MASP2 gene associated with low serum protease activity was found to be increased in Russians compared with Nenets and Dolgan-Nganasans (P < .001 and P = .03, respectively). The results of the current study and our previous findings corroborate with a hypothesis that human evolution has been directed toward the accumulation of genotypes associated with low activity of the lectin complement activation pathway.

Noncoding rare variants in PANX3 are associated with chronic back pain.

ABSTRACT: Back pain is the leading cause of years lived with disability worldwide, yet surprisingly, little is known regarding the biology underlying this condition. The impact of genetics is known for chronic back pain: its heritability is estimated to be at least 40%. Large genome-wide association studies have shown that common variation may account for up to 35% of chronic back pain heritability; rare variants may explain a portion of the heritability not explained by common variants. In this study, we performed the first gene-based association analysis of chronic back pain using UK Biobank imputed data including rare variants with moderate imputation quality. We discovered 2 genes, SOX5 and PANX3 , influencing chronic back pain. The SOX5 gene is a well-known back pain gene. The PANX3 gene has not previously been described as having a role in chronic back pain. We showed that the association of PANX3 with chronic back pain is driven by rare noncoding intronic polymorphisms. This result was replicated in an independent sample from UK Biobank and validated using a similar phenotype, dorsalgia, from FinnGen Biobank. We also found that the PANX3 gene is associated with intervertebral disk disorders. We can speculate that a possible mechanism of action of PANX3 on back pain is due to its effect on the intervertebral disks.

Insights into the pleiotropic relationships between chronic back pain and inflammation-related musculoskeletal conditions: rheumatoid arthritis and osteoporotic abnormalities.

ABSTRACT: The ageing process includes the development of debilitating musculoskeletal (MSK) conditions, including chronic back pain (CBP), rheumatoid arthritis (RA), and osteoporosis (OP). The mechanisms involved in the genetic-epidemiological relationships between these MSK phenotypes are controversial and limited and thus require clarification, in particular, between CBP and the other MSK phenotypes. A cross-sectional statistical analysis was conducted using Europeans from the UK Biobank data collection, including 73,794 CBP, 4883 RA, and 7153 OP cases as well as 242,216 calcaneus bone mineral density scores. C-reactive protein (CRP) was measured for 402,165 subjects in this sample. Genetic correlations were assessed to evaluate shared genetic background between traits. Mendelian randomization was performed to assess a causal relationship between CBP and RA and OP along with other risk factors, such as CRP. Colocalization analysis was conducted to identify shared pleiotropic regions between the examined traits. Bayesian modelling was performed to determine a potential pathway that may explain the interrelationships among these traits. Mendelian randomization analyses revealed that CRP causally predicts CBP only (ß = 0.183, 95% CI = 0.077-0.290, P -value = 0.001). Horizontally pleiotropy appeared to explain the relationship between CBP and RA and OP. Through colocalization analysis, several genomic regions emerged describing common genetic influences between CBP and its proposed risk factors, including HLA-DQA1/HLA-DQB1, APOE , SOX5, and MYH7B as well as Histone 1 genes. We speculate that among other factors, CBP and its MSK comorbidities may arise from common inflammatory mechanisms. Colocalized identified genes may aid in advancing or improving the mode of treatment in patients with CBP.

Genome-Wide Association Analysis of Over 170,000 Individuals from the UK Biobank Identifies Seven Loci Associated with Dietary Approaches to Stop Hypertension (DASH) Diet.

Diet is a modifiable risk factor for common chronic diseases and mental health disorders, and its effects are under partial genetic control. To estimate the impact of diet on individual health, most epidemiological and genetic studies have focused on individual aspects of dietary intake. However, analysing individual food groups in isolation does not capture the complexity of the whole diet pattern. Dietary indices enable a holistic estimation of diet and account for the intercorrelations between food and nutrients. In this study we performed the first ever genome-wide association study (GWA) including 173,701 individuals from the UK Biobank to identify genetic variants associated with the Dietary Approaches to Stop Hypertension (DASH) diet. DASH was calculated using the 24 h-recall questionnaire collected by UK Biobank. The GWA was performed using a linear mixed model implemented in BOLT-LMM. We identified seven independent single-nucleotide polymorphisms (SNPs) associated with DASH. Significant genetic correlations were observed between DASH and several educational traits with a significant enrichment for genes involved in the AMP-dependent protein kinase (AMPK) activation that controls the appetite by regulating the signalling in the hypothalamus. The colocalization analysis implicates genes involved in body mass index (BMI)/obesity and neuroticism (ARPP21, RP11-62H7.2, MFHAS1, RHEBL1). The Mendelian randomisation analysis suggested that increased DASH score, which reflect a healthy diet style, is causal of lower glucose, and insulin levels. These findings further our knowledge of the pathways underlying the relationship between diet and health outcomes. They may have significant implications for global public health and provide future dietary recommendations for the prevention of common chronic diseases.

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia.

BACKGROUND: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. METHODS: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. RESULTS: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. CONCLUSIONS: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients.

Causal effects of psychosocial factors on chronic back pain: a bidirectional Mendelian randomisation study.

PURPOSE: Risk factors for chronic back pain (CBP) may share underlying genetic factors, making them difficult to study using conventional methods. We conducted a bi-directional Mendelian randomisation (MR) study to examine the causal effects of risk factors (education, smoking, alcohol consumption, physical activity, sleep and depression) on CBP and the causal effect of CBP on the same risk factors. METHODS: Genetic instruments for risk factors and CBP were obtained from the largest published genome-wide association studies (GWAS) of risk factor traits conducted in individuals of European ancestry. We used inverse weighted variance meta-analysis (IVW), Causal Analysis Using Summary Effect (CAUSE) and sensitivity analyses to examine evidence for causal associations. We interpreted exposure-outcome associations as being consistent with a causal relationship if results with IVW or CAUSE were statistically significant after accounting for multiple statistical testing (p < 0.003), and the direction and magnitude of effect estimates were concordant between IVW, CAUSE, and sensitivity analyses. RESULTS: We found evidence for statistically significant causal associations between greater education (OR per 4.2 years of schooling = 0.54), ever smoking (OR = 1.27), greater alcohol consumption (OR = 1.29 per consumption category increase) and major depressive disorder (OR = 1.41) and risk of CBP. Conversely, we found evidence for significant causal associations between CBP and greater alcohol consumption (OR = 1.19) and between CBP and smoking (OR = 1.21). Other relationships did not meet our pre-defined criteria for causal association. CONCLUSION: Fewer years of schooling, smoking, greater alcohol consumption, and major depressive disorder increase the risk of CBP. CBP increases the risk of greater alcohol consumption and smoking.