Related Endophenotypes Research Articles

Associations of genetic variants for refractive error and axial length in adults with ocular endophenotypes in children: a cross-sectional and longitudinal study

AimsTo investigate the associations of genetic variants previously linked to axial length (AL) and spherical equivalent refraction (SE) in adults with refractive error and related endophenotypes in children, at baseline...

Genetic variability of FOXP2 and its targets CNTNAP2 and PRNP in frontotemporal dementia: A pilot study in a southern Italian population

The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify putative effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.

Causal relationships between Gut microbiota and primary open-angle Glaucoma: A Mendelian randomization and mediation analysis of Glaucoma endophenotypes

Primary open-angle glaucoma (POAG) is a widespread condition responsible for irreversible blindness, and its prevalence is expected to increase substantially in the coming decades. Despite its significance, the exact cause of POAG remains elusive, necessitating a comprehensive exploration of its pathogenesis. Emerging research suggests a potential link between alterations in gut microbiota composition and POAG. However, establishing causality in these associations remains a challenge.In this study, we employed Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota (GM) and POAG. Significant bacteria taxa were further analyzed with POAG endophenotypes. We utilized data from genome-wide association studies (GWAS) for GM and POAG, as well as for glaucoma endophenotypes, including intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, vertical cup-to-disc ratio (VCDR), and central corneal thickness (CCT). Univariable, multivariable MR and mediation effect analysis were conducted.Our analysis revealed that certain taxa, including phylum Euryarchaeota, genus Odoribacter, Rumnicoccaceae UCG009, Ruminiclostridium9, unknown genus id.2071, and Eubacterium rectale group, were associated with an increased risk of POAG. On the other hand, family Victivallaceae, Lacchnospiraceae, genus Lachnoclostridium, Oscillospira, Ruminococcaceae UCG011, Alloprevotella, and Faecalibacterium were found to be associated with a decreased risk of POAG. Furthermore, some of these taxa were found to be connected to glaucoma endophenotypes. Through further multivariable MR analysis, it was determined that IOP, VCDR, and CCT might played mediating roles between GM and POAG.In conclusion, this study utilizes MR analysis to elucidate potential causal associations between GM and POAG, providing insights into specific GM taxa that influence POAG risk and related endophenotypes. These findings emphasize the potential role of the gut microbiota in the pathogenesis of POAG and pave the way for future research and therapeutic interventions.

Association of DNA methylation from the temporal cortex and cerebellum with AD‐related neuropathology and biochemistry

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often measured by Thal phase and Braak stage, respectively. Frequently, Aβ also deposits in the brain vasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. Assessment of these and related endophenotypes can reveal biological insights into the phenotypic variability in AD. We hypothesize that, amongst AD patients, severity of neuropathology and brain levels of AD‐related proteins are influenced by variation in DNA methylation (DNAm), the identification of which may uncover biological pathways for AD pathogenesis. To test this, we performed epigenome‐wide association studies (EWAS) using DNAm from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathology measures (Braak, Thal, and CAA) and brain levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from autopsy‐confirmed AD cases available through the Mayo Clinic Brain Bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Bisulfite converted reads were sequenced on the Illumina High Seq4000 and quality filtered. Neuropathology scoring was performed by an experienced neuropathologist. TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Individual CpG methylation ratios were tested for association with each neuropathological and biochemical measure using the R package CpGassoc.ResultsWe identified multiple epigenome‐wide significant CpGs unique to each AD‐related measure. Comparisons between the TCX and CER revealed region specific CpG associations. The effects of sex, age at death, APOE genotype, and presence of genetic variants for each significant CpG association were also identified.ConclusionsAlthough all neuropathological and biochemical measures tested reflect core AD pathologies, our results demonstrate unique associations of epigenetic factors with these individual phenotypes, suggesting that their variability may be governed by distinct epigenetic processes. Discovery of DNAm changes that underlie specific neuropathological or biochemical outcomes can enhance our understanding of AD pathophysiology and may lead to the identification of novel gene or pathway targets for the different facets of this complex condition.

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

Exploring the shared genetic architecture of modifiable risk factors and related endophenotypes of Alzheimer’s disease: A genomic SEM study

AbstractBackgroundThe mechanisms by which modifiable risk factors influence Alzheimer’s disease (AD) remain incompletely understood. Previous work using linkage disequilibrium score regression (LDSC) indicates that many of the modifiable risk factors have high genetic correlation with one another. Modelling this shared genetic architecture between risk factors, associated endophenotypes and AD could yield important insights into shared aetiological pathways.MethodWe used genomic structural equation modelling (SEM) to model the shared genetic architecture between potentially modifiable risk factors (including anxiety, depression, diabetes, education, hearing loss, hypertension, obesity, sleep, smoking) and related endophenotypes (including inflammatory markers and metabolites). Genomic SEM uses summary statistics from genome‐wide association studies (downloaded from leading consortia, the Neale lab group, CTG lab group and UK Biobank) to calculate the genetic covariance between traits using multivariable LDSC. We then used exploratory factor analysis (EFA) to model the patterns of shared genetic architecture into latent constructs.ResultMultivariable LDSC showed multiple correlations between traits. EFA showed that AD shares genetic covariance with circulating metabolites and cytokines, but not modifiable risk factors. A second factor showed loadings of age‐related hearing loss with cytokines and metabolites distinct from their variance with Alzheimer’s disease. A third factor comprised the majority of other risk factors including depression, insomnia and smoking, but not diabetes or obesity, which did not share significant covariance with any other AD‐related traits.ConclusionWe found high levels of shared genetic architecture between AD risk factors that were not shared with AD itself. This could suggest that rather than a direct causal effect on AD, risk factors exert their influence via a common intermediary (e.g. pro‐inflammatory states and/or cognitive reserve). Further work is required to establish model fit statistics, identify common SNPs related to these factors and conduct multivariable Mendelian randomisation to measure causal pathways that could lead to AD. This approach could provide important biological insights into the mechanisms underpinning the shared genetic architecture of AD risk factors, and explore how variation at these loci functionally impacts on AD pathophysiology, elucidating aetiological pathways, and ultimately prioritising targets for drug discovery and efforts to prevent AD.

Working Memory as Endophenotypes in First-Degree Relatives of Children with Neurodevelopmental Disorders: An Indian Account

Working Memory as Endophenotypes in First-Degree Relatives of Children with Neurodevelopmental Disorders: An Indian Account

Association of CD14 with incident dementia and markers of brain aging and injury.

To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts. Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS. We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; p = 0.01) following adjustments for age, sex, APOE ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS. sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

Symposium 20: Closing in on mechanisms associated with the onset of psychiatric disorders and related endophenotypes: New findings emerging from biologically and developmentally-informed approaches: Time: Saturday, 31/Aug/2019: 4:30pm–6:00pmLocation: CartesioSession Chair: Isabelle Ouellet-Morin

Symposium 20: Closing in on mechanisms associated with the onset of psychiatric disorders and related endophenotypes: New findings emerging from biologically and developmentally-informed approaches: Time: Saturday, 31/Aug/2019: 4:30pm–6:00pmLocation: CartesioSession Chair: Isabelle Ouellet-Morin

Symposium 11: Impact of different characteristics of early adversity on stress related endophenotypes and mental health problems: Time: Saturday, 31/Aug/2019: 8:30am–10:00amLocation: CartesioSession Chair: Elif Aysimi DumanSession Chair: Andrea Danese

Symposium 11: Impact of different characteristics of early adversity on stress related endophenotypes and mental health problems: Time: Saturday, 31/Aug/2019: 8:30am–10:00amLocation: CartesioSession Chair: Elif Aysimi DumanSession Chair: Andrea Danese

Heritability of glaucoma and glaucoma-related endophenotypes: Systematic review and meta-analysis

We have systematically extracted all available heritability (h2) estimates of glaucoma and related endophenotypes from the literature and summarized the evidence by meta-analysis. Glaucoma endophenotypes were classified into 10 clusters: intraocular pressure, anterior chamber size, central corneal thickness, cup-to-disc ratio, disc size, cup size, corneal hysteresis, retinal nerve fiber layer thickness, cup shape, and peripapillary atrophy. Random-effects meta-analyses were performed for each cluster. For clusters with n ≥ 10 h2 estimates, we also performed subgroup and meta-regression analyses. The literature search yielded 53 studies. The h2 of primary open-angle glaucoma ranged from 0.17 to 0.81, and was 0.65 for primary angle-closure glaucoma in a single study. The pooled endophenotype h2 estimates were intraocular pressure, 0.43 (0.38–0.48); anterior chamber size, 0.67 (0.60–0.74); central corneal thickness, 0.81 (0.73–0.87); cup-to-disc ratio, 0.56 (0.44–0.68); disc size, 0.61 (0.37–0.81); cup size, 0.58 (0.35–0.78); corneal hysteresis, 0.40 (0.29–0.51); retinal nerve fiber layer thickness, 0.73 (0.42–0.91); cup shape, 0.62 (0.22–0.90); and peripapillary atrophy, 0.73 (0.70–0.75). We identified mean age, ethnicity, and study design as major sources of heterogeneity. Our results confirm the strong influence of genetic factors on glaucoma and its endophenotypes. These pooled h2 estimates provide the most accurate assessment to date of the total genetic variation that can ultimately be explained by gene-finding studies.

Assessment of Plasma Total Tau Level as a Predictive Biomarker for Dementia and Related Endophenotypes

Blood-based biomarkers have the potential to improve the identification of persons with the greatest dementia risk for inclusion in dementia prevention trials through low-cost and minimally invasive screening. To investigate the use of plasma total tau as a blood biomarker for dementia and related endophenotypes. This prospective cohort study used data from the US community-based Framingham Heart Study with replication in the Memento study, a multicenter cohort of persons with mild cognitive impairment or subjective cognitive complaints recruited from memory clinics across France. Total tau levels were measured from stored plasma samples in Framingham Heart Study participants during 2004 to 2011. Dementia follow-up occurred across a median of 6 years (interquartile range, 5-8 years) for persons 65 years and older who were dementia free at baseline. Plasma and/or cerebrospinal fluid samples were obtained from Memento study participants from April 19, 2011, to June 22, 2016. Dementia follow-up took place over a median of 4 years (interquartile range, 3-5 years). Data analysis was performed from January to November 2018. Plasma total tau level measured using single-molecule array technology. Incidence of dementia of any cause (all dementia) and dementia due to clinical Alzheimer disease (AD dementia). Among the 1453 participants in the Framingham dementia study sample, the mean (SD) age was 75 (7) years; 792 (54.5%) were female. Among the 367 individuals in the replication cohort, the mean (SD) age was 69 (9) years; 217 (59.1%) were female. Of 134 cases of incident all dementia in the Framingham sample, 105 were AD dementia. After adjustment for age and sex, each SD unit increase in the log of plasma total tau level was associated with a 35% increase in AD dementia risk (hazard ratio [HR], 1.35; 95% CI, 1.10-1.67). The addition of plasma total tau to a model including age and sex improved the stratification of participants for risk of AD dementia (net reclassification improvement, 0.382; 95% CI, 0.030-0.716). Higher plasma total tau level was associated with poorer cognition across 7 cognitive tasks (P < .05) and smaller hippocampi (hippocampal volume: β [SE] = 0.002 [0.001]; P = .003) as well as neurofibrillary tangles (β [SE] = 0.95 [0.45]; P = .04) and microinfarcts (odds ratio, 3.04; 95% CI, 1.26-7.37) at autopsy. In the replication cohort, plasma total tau level weakly correlated with cerebrospinal fluid total tau level (Spearman correlation coefficient, 0.16; P = .07), but plasma total tau was at least as strongly associated with incident AD dementia as cerebrospinal fluid total tau (log plasma total tau: HR, 2.33; 95% CI, 1.00-5.48; log cerebrospinal fluid total tau: HR, 2.14; 95% CI, 1.33-3.44) after adjustment for age and sex. The findings suggest that plasma total tau levels may improve the prediction of future dementia, are associated with dementia endophenotypes, and may be used as a biomarker for risk stratification in dementia prevention trials.

SA49 - A QUANTITATIVE ANALYSIS OF DISCREPANCIES BETWEEN CANDIDATE GENE AND GENOME-WIDE STUDIES OF COMPLEX TRAITS AND RELATED ENDOPHENOTYPES

Background Candidate gene and genome-wide investigations of complex traits and related endophenotypes are both fundamentally concerned with elucidating the biological pathways underlying individual differences in behavior. However, these two methods have produced disparate literatures and have often reached contradictory conclusions about the genetic architectures of target traits. Thus far, the polarizing attempts to reconcile these discrepancies have been largely rhetorical. In contrast, the present research uses rigorous quantitative methods to evaluate plausible explanations for the current disagreement in the literature: poor measurement and simplistic models in genome-wide studies versus publication bias and methodological errors in candidate gene work. Results aim to aid investigators in parsing previous findings and selecting future research targets. Methods We present closed form representations of the dependencies between statistical power in genome-wide association studies and endophenotype studies, measurement error, and endotype-complex trait associations. The resulting theory is used to critically evaluate the existing candidate gene literature. Additionally, we present novel methods for falsifying gene-by-environment interaction hypotheses in genome-wide samples where the environmental variable is unobserved and apply this method to data from large genome-wide studies of Schizophrenia and Major Depressive Disorder conducted by the Psychiatric Genetics Consortium. Finally, we evaluate the evidence for publication bias in the candidate gene literature as a competing explanation for observed discrepancies. Results Attenuation of true genetic associations in genome-wide studies vis-a-vis those reported in smaller candidate gene studies (regardless of whether caused by measurement error, biological distance, or any combination thereof) is only likely to explain observed discrepancies in the literature when the association between the candidate-gene study trait and the genome-wide association study trait is weak, leaving endophenotype candidate gene researchers in a paradoxical position. Moreover, even after allowing for the possibility of extreme measurement error in genome-wide data, leading candidate gene-by-environment interaction hypotheses are incompatible with recent genome-wide association study findings. Finally, an overwhelming ratio of positive to null findings and the ubiquitous failure to cite mainstream genetics findings suggest that prevalent publication bias and interdisciplinary fragmentation characterize the existing candidate gene literature. Discussion Candidate gene research, especially endophenotype and gene-by-environment interaction literature continue to gain popularity across the behavioral sciences. However, empirical support for the findings these methods have produced is weak. By making common arguments for continuing candidate gene research mathematically precise and then evaluating evidence for their unacknowledged implications, we conclude that neither measurement error, overly-complex or heterogenous phenotyping, nor unmeasured environmental moderators can explain discrepancies between candidate gene and genome-wide findings. Instead, widespread publication bias and false positive findings provide a likely alternative explanation.

M101 - THE DISC1 GENE AND MAJOR MENTAL ILLNESS IN FINLAND

Background Linkage and association studies of major mental illness in Finland have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and variants in the DISC1 gene have been associated with Schizophrenia (SCZ), bipolar disorder, and autism spectrum disorders, as well as to variations in related endophenotypes such as visual working memory, anhedonia, and gray matter volume in the dorsal lateral prefrontal cortex. Despite this consistent line of evidence for these loci in the Finnish population, any true causal variants within the DISC1 gene are yet to be identified. Methods To identify any potential mutations, a subset of families ascertained for SCZ (n=20 families, 96 individuals) were sequenced using Nimblegen SeqCap EZ for the DISC1 gene locus, including TSNAX. All identified variants were then prioritized using association analysis (p Results With the aid of this three-step sequencing and genotyping approach, we identified 1,828 variants in the DISC1 gene, of which 28 variants were identified as associated (p Discussion We aim to identify the potential mutations within the DISC1 gene which have been alluded to through our previous studies of Finnish cohorts for major mental illness. Our initial findings confirm the observation of association for several variants in the DISC1 gene for varied phenotypes, while focusing on the specific variants that have potential functional consequences. The variants we report may represent the principal major mental illness mutations within the DISC1 gene in the Finnish population. Once the relevance of these mutations to multiple diagnostic criteria is determined, we will study these mutations with respect to alternative phenotypes to the diagnoses available in these cohorts, including neuropsychological endophenotypes, neuroimaging, gene expression levels from lymphocytes, and medication usage.

Exome Sequencing and Genomic Studies To Better Understand Alcohol Dependence

The Collaborative Study on the Genetics of Alcoholism (COGA) has focused on studies of large families with multiple alcoholic members. We have conducted genome-wide association studies (GWAS) to identify common variants that affect risk for alcohol dependence and related phenotypes, including electrophysiological endophenotypes. Because we have studied families from different ethnic groups, we are meta-analyzing our results across these groups. We are also contributing to larger meta-analyses through the Psychiatric Genomics Consortium.Recently, we have turned to exome sequencing of key affected individuals in these families to discover rare variants that may have stronger influences on risk, as well as on related endophenotypes. We developed a new phenotype to complement the DSM diagnostic phenotype; it includes items related to heavy drinking and its biological consequences. We used this new quantitative phenotype in order to select the more severe cases among those who met DSM-IV criteria for this sequencing. Studying large, densely affected families has several advantages: a) they are more likely to carry variants conferring risk, b) segregation of the variants within a family provides support for their contribution to risk and c) having GWAS data on the same families allows imputation of even rare variants for family members who are not sequenced.Functional studies are an important complement to the genetic studies. We have conducted RNA sequencing to examine the effects of controlled ethanol exposure on gene expression in lymphoblastoid cell lines from some of the COGA subjects. Measuring gene expression in the paired (exposed and unexposed) samples is a powerful design. We are also examining differences between alcoholics and controls in gene expression in several brain regions. In addition, we are investigating the biological effects of transitioning from abstinence or very little drinking to heavy drinking during adolescence and young adulthood. This involves examining differences in gene expression and DNA methylation in blood samples taken 2 years apart (before and after the transition), comparing adolescents who have transitioned to heavy drinking during those years to an age- and sex-matched control group who have not.Bringing together different approaches (common variants, rare variants, and functional studies) will help us better understand alcohol use disorders.

Depressive symptoms are associated with a functional polymorphism in a miR-433 binding site in the FGF20 gene

Genetic studies of major depressive disorder and its associated endophenotypes are useful for the identification of candidate genes. In recent years, variations in non-coding RNA genes, such as miRNAs, have been explored as novel candidates for psychiatric disorders and related endophenotypes. The aim of the present study was to evaluate the possible association between a functional polymorphism (rs12720208) in the FGF20 gene, which regulates its modulation by miR-433, and depressive symptoms in young adults. A sample of 270 participants from Colombia were evaluated with the Hospital Anxiety and Depression Scale - Depression Subscale (HADS-D) and genotyped for the rs12720208 polymorphism using a TaqMan assay. A lineal regression analysis was used. A statistically significant association of the functional polymorphism in the FGF20 gene (rs12720208) with depressive symptoms was found. It was observed that individuals with the G/A genotype had higher scores for the HADS-D subscale. Our results are the first description in the scientific literature about a significant association between a functional polymorphism in the FGF20 gene, which regulates its modulation by miR-433, and depressive symptoms.

MTHFR gene methylation is associated with perceived stress in healthy young adults.

Epigenetic factors have been identified in the past years as interesting candidates for psychiatric disorders and related endophenotypes. It has been found that the methylenetetrahydrofolate reductase (MTHFR) gene is associated with major depressive disorder, and the aim of the current study was to examine the possible association between perceived stress and MTHFR methylation, taking into account depressive symptoms as a covariate. Seventy-eight healthy Colombian participants (mean age=20.9 years; SD=3.0) were evaluated with the Perceived Stress Scale and with the Patient Health Questionnaire-9 for depressive symptomatology. MTHFR methylation levels were measured with a methylation-sensitive high-resolution melting method. A multiple regression analysis (adjusting for age, sex, and depressive symptoms) was carried out to assess the association between MTHFR methylation and perceived stress scores. We found a significant inverse correlation between MTHFR methylation levels and perceived stress scores (r=-0.502; P=5.9×10(-5)), which remained significant after being adjusted for age, sex, and depressive symptomatology. To our knowledge, this is the first study that reports an association between perceived stress and MTHFR methylation levels. This report adds evidence to the emerging role of epigenetic changes in endophenotypes related to affective disorders.

Heritability of glaucoma and glaucoma-related endophenotypes: systematic review and meta-analysis protocol

IntroductionGlaucoma is the second leading cause of age-related vision loss worldwide; it is an umbrella term that is used to describe a set of complex ocular disorders with a multifactorial...

Contribution of Genetic Polymorphisms and Haplotypes in DRD2, BDNF, and Opioid Receptors to Heroin Dependence and Endophenotypes Among the Han Chinese.

Heroin and drug dependence are major contributors to global health burden worldwide, but their underlying mechanisms remain elusive and may vary from population to population. Reward- and memory-related candidate genes dopamine D2 receptor (DRD2) and brain-derived neurotrophic factor (BDNF), as well as the opioid receptor genes (OPRM1, OPRD1, and OPRK1), have been implicated in drug dependence, but relatively little is known on their contributions to heroin dependence in populations worldwide. Hence, we evaluated the contributions of the above five candidate genes in heroin dependence and several important related endophenotypes (the onset age of heroin use and subjective response to first heroin use), at single single-nucleotide polymorphism as well as haplotype levels, in a Han Chinese population sample. We genotyped 546 unrelated and heroin-dependent subjects for the candidate genes noted, and 228 sex- and age-matched unrelated controls. The G allele of rs4654327 (OPRD1), DRD2 haplotype block CCGCCGTT (rs6277-rs1076560-rs2283265-rs2734833-rs2075652-rs1079596-rs4436578-rs11214607), and OPRD1 haplotypes TACG (rs6669447-rs2236857-rs508448-rs4654327), CG (rs508448-rs4654327), and TG (rs6669447-rs4654327) were significantly associated with heroin dependence phenotype. Homozygotes AA at rs6265 (BDNF), TT at rs16917234 (BDNF), and CC at rs508448 (OPRD1) also appeared as risk factors for the endophenotype earlier age of onset for heroin use. Two OPRM1 haplotypes, AG (rs1799971-rs1381376) and AT (rs1799971-rs3778151), were observed as potential protective factors. These emerging findings contribute to the literature on genetic biomarkers of drug dependence and related endophenotypes, and call for replication in independent population.