Sex effects on DNA methylation affect discovery in epigenome-wide association study of schizophrenia.

Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.

Identification of novel genomic loci for anxiety symptoms and extensive genetic overlap with psychiatric disorders.

AIMS: Anxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders. METHODS: We included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders. RESULTS: Anxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k-11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD n = 47 $$ \left(n=47\right) $$ , BIP n = 33 $$ \left(n=33\right) $$ , SCZ n = 71 $$ \left(n=71\right) $$ , ADHD n = 20 $$ \left(n=20\right) $$ , and ASD n = 5 $$ \left(n=5\right) $$ . Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci. CONCLUSIONS: Anxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

Prenatal social support in low-risk pregnancy shapes placental epigenome.

BACKGROUND: Poor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans. METHODS: In a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta. RESULTS: The mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22-25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies. CONCLUSIONS: The findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes. TRIAL REGISTRATION: NCT00912132 ( ClinicalTrials.gov ).

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression.

Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity and mortality. The causes underlying this relationship are poorly understood. Although these conditions are highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, schizophrenia (SCZ), bipolar disorder (BD) and major depression (MD) of European ancestry. Next, we characterized the identified shared loci using biological annotation resources. OUD data were obtained from the Million Veteran Program, Yale-Penn and Study of Addiction: Genetics and Environment (SAGE) (15 756 cases, 99 039 controls). SCZ (53 386 cases, 77 258 controls), BD (41 917 cases, 371 549 controls) and MD (170 756 cases, 329 443 controls) data were provided by the Psychiatric Genomics Consortium. We discovered genetic enrichment for OUD conditional on associations with SCZ, BD, MD and vice versa, indicating polygenic overlap with identification of 14 novel OUD loci at condFDR < 0.05 and 7 unique loci shared between OUD and SCZ (n = 2), BD (n = 2) and MD (n = 7) at conjFDR < 0.05 with concordant effect directions, in line with estimated positive genetic correlations. Two loci were novel for OUD, one for BD and one for MD. Three OUD risk loci were shared with more than one psychiatric disorder, at DRD2 on chromosome 11 (BD and MD), at FURIN on chromosome 15 (SCZ, BD and MD) and at the major histocompatibility complex region (SCZ and MD). Our findings provide new insights into the shared genetic architecture between OUD and SCZ, BD and MD, indicating a complex genetic relationship, suggesting overlapping neurobiological pathways.

Renal function in Ethiopian HIV-positive adults on antiretroviral treatment with and without tenofovir.

BACKGROUND: Limited data are available on the effect of antiretroviral treatment (ART) or Tenofovir disoproxil fumarate (TDF) on renal function in Ethiopians. We aimed to assess factors associated with renal function changes during the first year of ART with special focus on TDF. METHODS: HIV positive persons who were ≥ 18 years of age and eligible for ART initiation were recruited. Creatinine measurement to estimate glomerular filtration rate (eGFR) and spot urine analyses were performed at baseline and after 3, 6 and 12 months of ART. Univariate and multivariate linear regression and univariate logistic regression were used to determine factors associated with eGFR as continuous and categorical variable respectively. A linear mixed model was used to assess 12 month eGFR difference in TDF and non-TDF based regimen. RESULT: Of 340 ART-naïve HIV patients with baseline renal function tests, 82.3% (279/339) were initiated on a TDF based ART regimen. All patients were on non-nucleoside reverse transcriptase inhibitors (NNRTI) based ART regimen. The median (IQR) change in eGFR with 12 months of ART was 0.8 (- 11.1; 10.0) ml/min/1.73m2. About 41 and 26.9% of HIV patients had a drop of greater than 3 and 10 mL/min/1.73 m2 in eGFR at 12 month, respectively. However, none of the HIV patients declined to < 60 ml/min/1.73m2 within 12 months. Moreover, none of the HIV patients had persistent proteinuria or glycosuria. Older HIV patients especially age > 45 years and those with unsuppressed viral load at 6 month of ART had a significantly lower eGFR at 12 months of ART initiation. However, there was no difference in 12 month eGFR between HIV patients initiated on TDF based regimen and non-TDF based regimen. CONCLUSION: Renal function remained stable with no difference between HIV patients treated with TDF or non-TDF NNRTI based ART regimen over 12 months. However, older HIV patients and those with unsuppressed viral load deserve special focus on renal monitoring. Data on long-term safety of TDF (> 1 year) is still warranted in this population.

Taste the Pain: The Role of TRP Channels in Pain and Taste Perception.

Transient receptor potential (TRP) channels are a superfamily of cation transmembrane proteins that are expressed in many tissues and respond to many sensory stimuli. TRP channels play a role in sensory signaling for taste, thermosensation, mechanosensation, and nociception. Activation of TRP channels (e.g., TRPM5) in taste receptors by food/chemicals (e.g., capsaicin) is essential in the acquisition of nutrients, which fuel metabolism, growth, and development. Pain signals from these nociceptors are essential for harm avoidance. Dysfunctional TRP channels have been associated with neuropathic pain, inflammation, and reduced ability to detect taste stimuli. Humans have long recognized the relationship between taste and pain. However, the mechanisms and relationship among these taste-pain sensorial experiences are not fully understood. This article provides a narrative review of literature examining the role of TRP channels on taste and pain perception. Genomic variability in the TRPV1 gene has been associated with alterations in various pain conditions. Moreover, polymorphisms of the TRPV1 gene have been associated with alterations in salty taste sensitivity and salt preference. Studies of genetic variations in TRP genes or modulation of TRP pathways may increase our understanding of the shared biological mediators of pain and taste, leading to therapeutic interventions to treat many diseases.

Body Composition during Early Infancy and Mental Health Outcomes at 5 Years of Age: A Prospective Cohort Study of Ethiopian Children.

OBJECTIVE: To examine the relationship between body composition-specifically fat mass (FM) and fat-free mass (FFM)-in early infancy, and mental health outcomes in early childhood. STUDY DESIGN: In the Infant Anthropometry and Body Composition birth cohort study from Ethiopia, body composition was measured at birth and 1.5, 2.5, 3.5, 4.5, and 6 months of age. Mental health was assessed at 5 years of age using the approved Amharic version of the Strengths and Difficulties Questionnaire (SDQ), a parent report scale covering 4 different domains providing a total difficulties score. The associations of FM or FFM at birth as well as during early infancy, with SDQ score at 5 years of age were examined using multiple linear regression analyses. RESULTS: At 5 years of age, the mean ± SD for SDQ score was 10.4 ± 5.8. FM at birth was positively and FFM negatively associated with SDQ score. For each kg increase in FM at birth, the SDQ score at 5 years was 5.7 points higher (ß = 5.7; 95% CI, 1.4-10.0). In contrast, for each kilogram increase in FFM at birth, the SDQ score was 3.9 points lower (ß = -3.9; 95% CI, -7.0 to -0.8). Neither FM nor FFM accretion rate during early infancy were associated with SDQ score at 5 years of age. CONCLUSIONS: Fetal rather than infant body composition was associated with SDQ score at 5 years of age. Greater FFM accretion during fetal life may have contributed to more optimal neurobehavioral development during early life. However, the potential mechanisms underlying the observed associations need further investigation.

Body composition during early infancy and developmental progression from 1 to 5 years of age: the Infant Anthropometry and Body Composition (iABC) cohort study among Ethiopian children.

Early nutrition and growth have been found to be important early exposures for later development. Studies of crude growth in terms of weight and length/height, however, cannot elucidate how body composition (BC) might mediate associations between nutrition and later development. In this study, we aimed to examine the relation between fat mass (FM) or fat-free mass (FFM) tissues at birth and their accretion during early infancy, and later developmental progression. In a birth cohort from Ethiopia, 455 children who have BC measurement at birth and 416 who have standardised rate of BC growth during infancy were followed up for outcome variable, and were included in the statistical analysis. The study sample was restricted to mothers living in Jimma town who gave birth to a term baby with a birth weight ≥1500 g and no evident congenital anomalies. The relationship between the exposure and outcome variables was examined using linear-mixed regression model. The finding revealed that FFM at birth was positively associated with global developmental progression from 1 to 5 years (ß=1·75; 95 % CI 0·11, 3·39) and from 4 to 5 years (ß=1·34; 95 % CI 0·23, 2·44) in the adjusted model. Furthermore, the rate of postnatal FFM tissue accretion was positively associated with development at 1 year of age (ß=0·50; 95 % CI 0·01, 0·99). Neither fetal nor postnatal FM showed a significant association. In conclusion, fetal, rather than postnatal, FFM tissue accretion was associated with developmental progression. Intervention studies are needed to assess whether nutrition interventions increasing FFM also increase cognitive development.

Challenges of bacterial meningitis case management in low income settings: an experience from Ethiopia.

OBJECTIVE: To investigate the current diagnostic and therapeutic strategies used in the care of patients with suspected bacterial meningitis at teaching hospitals in Ethiopia. METHODS: This was a hospital-based retrospective study conducted at four teaching hospitals in different regions of Ethiopia. Participants were patients aged 14 years and older treated for suspected bacterial meningitis. Presenting complaints, diagnostic strategies used and treatments given were obtained from clinical records. RESULT: A total of 425 patients were included in the study; 52.7% were men and 83.8% were younger than 50 years. Fever, headache, neck stiffness and impaired consciousness were the most common clinical presentations; 55.5% underwent lumbar puncture. Overall, only 96 (22.6%) patients had cerebrospinal fluid abnormalities compatible with bacterial meningitis. A causative bacterium was identified in only 14 cases. Ceftriaxone was used as the empiric treatment of choice, either alone or in combination with other antibiotics; 17.6% of patients were also given vancomycin. Adjunctive dexamethasone was given to 50.4%. CONCLUSION: Most patients treated as bacterial meningitis did not receive a proper diagnostic workup. The choice of antibiotic was not tailored to the specific clinical condition of the patient. Such an approach may result in poor treatment outcomes and lead to antibiotic resistance. Management of patients with suspected bacterial meningitis should be supported by analysis of cerebrospinal fluid, and treatment should be tailored to local evidence and current evidence-based recommendations.

The effect of nutritional supplementation on quality of life in people living with HIV: a randomised controlled trial.

OBJECTIVE: To determine the effects of lipid-based nutrient supplements (LNS) on the quality of life of people living with HIV (PLHIV) during the first 3 months of antiretroviral treatment (ART) and to investigate the effects of timing of supplementation by comparing with supplementation during the subsequent 3 months. METHODS: A randomised controlled trial was conducted in three ART clinics within public health facilities in Jimma, Ethiopia. Participants were PLHIV eligible to start ART with body mass index >17 kg/m(2) and given daily supplements of 200 g of LNS containing whey or soya either during the first 3 months or the subsequent months of ART. The outcome was measured in terms of total quality-of-life scores on the adapted version of the WHOQOL-HIV-BREF assessed at baseline, three and six months. RESULTS: Of the 282 participants, 186 (66.0%) were women. The mean age (SD) was 32.8 (±9.0) years, and the mean (SD) total quality-of-life score was 82.0 (±14.8) at baseline assessment. At 3 months, participants who received LNS showed better quality of life than those who only received ART without LNS (ß = 6.2, 95% CI: 2.9: 9.6). At 6 months, there was no difference in total quality-of-life score between the early and delayed supplementation groups (ß = 3.0, 95% CI: -0.4: 6.4). However, the early supplementation group showed higher scores on the social and spirituality domains than the delayed group. CONCLUSIONS: LNS given during the first three months of ART improves the quality of life of PLHIV.