Genome-wide analyses of common and rare genetic variations have documented the heritability of major psychiatric disorders, established their highly polygenic genetic architecture, and identified ...hundreds of contributing variants. In recent years, these studies have illuminated another key feature of the genetic basis of psychiatric disorders: the important role and pervasive nature of pleiotropy. It is now clear that a substantial fraction of genetic influences on psychopathology transcend clinical diagnostic boundaries. In this review, we summarize evidence in psychiatry for pleiotropy at multiple levels of analysis: from overall genome-wide correlation to biological pathways and down to the level of individual loci. We examine underlying mechanisms of observed pleiotropy, including genetic effects on neurodevelopment, diverse actions of regulatory elements, mediated effects, and spurious associations of genomic variation with multiple phenotypes. We conclude with an exploration of the implications of pleiotropy for understanding the genetic basis of psychiatric disorders, informing nosology, and advancing the aims of precision psychiatry and genomic medicine.
Obesity has been associated with cognition in observational studies; however, whether its effect is confounding or a reverse causality remains inconclusive. This study aimed to investigate the causal ...relationships of overall obesity, measured by body mass index (BMI), and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), and cognition across European and Asian populations using Mendelian randomization (MR) analysis.
We used publicly available genome-wide association study (GWAS) summary data of European ancestry, including BMI (n = 322,154) and WHRadjBMI (n = 210,088) from the GIANT consortium, and cognition performance (n = 257,828) from the UK Biobank and COGENT consortium. Data for individuals of Asian ancestry were retrieved from Taiwan Biobank to perform GWAS for BMI (n = 65,689), WHRadjBMI (n = 65,683), and Mini-Mental State Examination (MMSE, n = 21,273). MR analysis was carried out using the inverse-variance weighted method for the main results. Further, we examined the overall pleiotropy by MR-Egger intercept, and detected and adjusted for possible outliers using MR PRESSO.
No causal effect of BMI on cognition performance (beta 95% CI = 0.00 -0.07, 0.07, p value = 0.91) was found for Europeans; however, a 1-SD increase in WHRadjBMI was associated with a 0.07 standardized score decrease in cognition performance (beta 95% CI = -0.07 -0.12, -0.02, p value = 0.006). Further, no causal effect of BMI on MMSE (beta 95% CI = 0.01 -0.08, 0.10, p = 0.91) was found for Asians; however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized score decrease in MMSE (beta 95% CI = -0.17 -0.30, -0.03, p = 0.02). In both populations, overall pleiotropy was not detected, and outliers did not affect the robustness of the main findings.
This trans-ethnic MR study reveals that abdominal adiposity, as measured by WHR adjusted for BMI, impairs cognition, whereas weak evidence suggests that BMI impairs cognition.
IMPORTANCE: Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical ...laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression. OBJECTIVE: To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center’s biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent. EXPOSURES: Depression polygenic scores. MAIN OUTCOMES AND MEASURES: White blood cell count. RESULTS: Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 range, birth-90.0 years). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (β, 0.03; SE, 0.004; P = 1.07 × 10−17), which was replicated in a meta-analysis across the 4 health care systems (β, 0.03; SE, 0.002; P = 1.03 × 10−136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10−70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10−44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts. CONCLUSIONS AND RELEVANCE: This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.
Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting ...a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets.
Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed.
Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval CI: 0.0042–0.0076%), 1.7–3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin.
The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.
As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly ...penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes.
Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10
), LDLR (P = 3.6 × 10
), and CACNA1S (P = 5.8 × 10
). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10
), and APOB and tobacco use disorder (P = 1.1 × 10
).
Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionDisruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. ...Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms.Research design and methodsThis study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10–14 weeks) and visit 1 (15–26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson’s partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits.ResultsLipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR) <0.05). Among individual lipids, 58 metabolites at visit 0 and 96 metabolites at visit 1 (40 metabolites at both time points) significantly differed between women who developed GDM and who did not (FDR <0.05). Furthermore, GDM-related lipid networks and individual lipids showed consistent correlations with maternal glycemic markers particularly in early pregnancy at visit 0.ConclusionsPlasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk in race/ethnically diverse US women. Future research is warranted to assess lipid metabolites as etiologic markers of GDM.
Polygenic risk scores (PRS) measure genetic disease susceptibility by combining risk effects across the genome. For coronary artery disease (CAD), type 2 diabetes (T2D), and breast and prostate ...cancer, we performed cross-ancestry evaluation of genome-wide PRSs in six biobanks in Europe, the United States, and Asia. We studied transferability of these highly polygenic, genome-wide PRSs across global ancestries, within European populations with different health-care systems, and local population substructures in a population isolate. All four PRSs had similar accuracy across European and Asian populations, with poorer transferability in the smaller group of individuals of African ancestry. The PRSs had highly similar effect sizes in different populations of European ancestry, and in early- and late-settlement regions with different recent population bottlenecks in Finland. Comparing genome-wide PRSs to PRSs containing a smaller number of variants, the highly polygenic, genome-wide PRSs generally displayed higher effect sizes and better transferability across global ancestries. Our findings indicate that in the populations investigated, the current genome-wide polygenic scores for common diseases have potential for clinical utility within different health-care settings for individuals of European ancestry, but that the utility in individuals of African ancestry is currently much lower.
•An evaluation of cross-ancestry transferability of polygenic risk scores•Four common diseases in four global ancestry groups and across Europe were studied•PRS transferability was high across European ancestry and lowest for African ancestry•PRS transferability was good across population substructures in Finland
Combining six biobanks in Europe, the United States, and Asia, Mars et al. evaluated cross-ancestry transferability of polygenic risk scores for four common diseases: coronary artery disease, type 2 diabetes, and breast and prostate cancer. They observed good cross-ancestry transferability between individuals with different European ancestry, but poorer transferability in individuals of African, South Asian, and East Asian ancestry, which highlights the need for diversity in polygenic risk score development for clinical translation.
Abstract
Cigarette smoking has been suggested to be associated with the risk of schizophrenia in observational studies. A significant causal effect of smoking on schizophrenia has been reported in ...European populations using the Mendelian randomization approach; however, no evidence of causality was found in participants from East Asia. Using Taiwan Biobank (TWBB), we conducted genome-wide association studies (GWAS) to identify susceptibility loci for smoking behaviors, including smoking initiation (
N
= 79,989) and the onset age (
N
= 15,582). We then meta-analyzed GWAS from TWBB and Biobank Japan (BBJ) with the total sample size of 245,425 for smoking initiation and 46,000 for onset age of smoking. The GWAS for schizophrenia was taken from the East Asia Psychiatric Genomics Consortium, which included 22,778 cases and 35,362 controls. We performed a two-sample Mendelian randomization to estimate the causality of smoking behaviors on schizophrenia in East Asia. In TWBB, we identified one locus that met genome-wide significance for onset age. In a meta-analysis of TWBB and BBJ, we identified two loci for smoking initiation. In Mendelian randomization, genetically predicted smoking initiation (odds ratio (OR) = 4.00, 95% confidence interval (CI) = 0.89–18.01,
P
= 0.071) and onset age (OR for a per-year increase = 0.96, 95% CI = 0.91–1.01,
P
= 0.098) were not significantly associated with schizophrenia; the direction of effect was consistent with European Ancestry samples, which had higher statistical power. These findings provide tentative evidence consistent with a causal role of smoking on the development of schizophrenia in East Asian populations.
Although Taiwan has implemented several important interventions for various HIV-at-risk populations to combat the HIV epidemic, little is known regarding AIDS incidence at presentation and during ...follow-up among the various HIV-at-risk populations in Taiwan. A better understanding of AIDS incidence trends would help improve patient care and optimize public health strategies aimed at further decreasing HIV-related morbidity and mortality.
Data from Taiwan Centers for Disease Control-operated Notifiable Diseases Surveillance System and Taiwan National Health Insurance Research Database (1998-2012) was divided into five cohort periods (consecutive 3-year groups). Logistic regression was employed to identify factors associated with AIDS incidence at presentation. Time-dependent Cox regression was used to identify factors associated with AIDS incidence during the follow-up period.
Of 22,665 patients mean age: 32 years; male (93.03%), 6210 (27.4%) had AIDS incidence over 2 (1.16) median (interquartile range) years of follow-up. AIDS developed in ≤3 months of HIV diagnosis in 73.6% AIDS patients. AIDS incidence trends at presentation and during follow-up differed according to HIV transmission routes over the five periods: AIDS at presentation increased in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.648 for bisexuals) but decreased to a nadir in period 3 and then increased slightly in period 5 (P < 0.001) in people who injected drugs (PWIDs). AIDS incidence during the follow-up period increased from period 1 to a peak in period 3 or 4, before declining slightly in period 5, in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.549 for bisexuals). However, it increased throughout the five periods in PWIDs (P < 0.001). Older age, sexual contact group versus PWIDs, high versus low income level, cohort periods, and HIV diagnosis regions helped predict AIDS at presentation and during follow-up.
Disparities in AIDS incidence trends in various HIV-at-risk populations reflect different sociodemographic variables of HIV exposure and the adopted HIV prevention strategies. This study suggests the urgent need for tailored strategies aimed at specific populations at presentation and during follow-up.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To develop a method for estimating cell-specific effects in epigenomic association studies in the presence of cell type heterogeneity.
We utilized Monte Carlo Expectation-Maximization algorithm with ...Metropolis-Hastings sampler to reconstruct the 'missing' cell-specific methylations and to estimate their associations with phenotypes free of confounding by cell type proportions.
Simulations showed reliable performance of the method under various settings including when the cell type is rare. Application to a real dataset recapitulated the directly measured cell-specific methylation pattern in whole blood.
This work provides a framework to identify important cell groups and account for cell type composition useful for studying the role of epigenetic changes in human traits and diseases.
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