Cognitive performance and normative data between Hispanic and non-Hispanic cohorts: Results from the South Texas Alzheimer’s Disease Research Center (ADRC)

Background: The prevalence of Alzheimer\u27s disease and related dementias (ADRD) in the United States was estimated as 6.5 million people in 2022, with a five-fold increase for the Hispanic/Latinx population expected by 2060. The South Texas Alzheimer\u27s Disease Center (STAC) was designated as a new ADRC in 2021 by the National Institute on Aging (NIA) with a specific aim to serve the growing needs of the local underrepresented Hispanic population. As cultural and linguistic factors can impact performance on cognitive tests, the goal of the study was to compare UDS-3 cognitive test raw scores and normative data in Hispanic and non-Hispanic adults without cognitive impairment residing in South Texas. Method: Participants from the STAC cohort completed the Uniform Data Set (UDS), V.3.0, which includes demographics and neuropsychological battery. All batteries were administered in the participants’ preferred language, English. Normative data was calculated using Weintraub et al. (2018)’s age, sex, and education adjusted regression models for UDSNB 3.0. Mean differences between baseline visit raw scores and normative data were compared using independent sample t-tests among Hispanic and non-Hispanic participants. Result: Thirty-four Hispanic (mean age=70.4, 67.6% female) and thirty-eight non-Hispanic (mean age=71.9, 57.9% female) participants were included. Hispanic participants had fewer years of education relative to non-Hispanic participants [M(SD)] = [14.7(2.5)] to [16.5(2.5)], respectively; (t(70.1)=3.0, p =0.004); although, the groups did not differ in age or sex distribution (p\u3e0.05). Hispanic and non-Hispanic participants generally performed equivalently on the neuropsychological battery. However, Hispanics had lower mean raw scores on the Montreal Cognitive Assessment (MoCA) (t(70.8)= 3.6, p Conclusion: Overall, Hispanic and non-Hispanic participants performed similarly on the UDS-3 neuropsychological battery. However, Hispanics had lower mean raw and normative scores on the MINT, as well as the MoCA which also includes language measures. Our findings highlight the importance of future research validating the sensitivity and specificity of normative data used in underrepresented populations, especially those at higher risk for ADRD

Publisher Correction: Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development

Los polimorfismos de IL-10, IFN-? e IL-1? influyen en el desarrollo de OT en una población colombiana

Antecedentes: la toxoplasmosis es causada por una infección con el parásito protozoario Toxoplasma gondii, que tiene la capacidad de infectar a todos los animales de sangre caliente en todo el mundo. Se estima que el 30-70% de la población humana está infectada con este parásito, y esencialmente toda la población humana está en riesgo de infección. Un número limitado de personas desarrolla síntomas, lo que sugiere que la susceptibilidad del huésped y la disparidad de tensión pueden desempeñar un papel en la variabilidad de los síntomas clínicos. La toxoplasmosis es una causa importante de defectos visuales en la población colombiana, sin embargo, la asociación entre polimorfismos genéticos en los genes de citoquinas y la susceptibilidad a la toxoplasmosis ocular no se ha estudiado en esta población. Métodos y materiales: este trabajo evalúa las asociaciones entre polimorfismos en los genes que codifican las citoquinas TNF-? (rs1799964, rs1800629, rs1799724, rs1800630, rs361525); IL-1? (rs16944, rs1143634, rs1143627), IL-1? (rs1800587); IFN-? (rs2430561); IL-10 (rs1800896, rs1800871) y la presencia de toxoplasmosis ocular (OT) en una muestra de población colombiana (61 pacientes con OT y 116 controles sanos). El genotipado se realizó con la técnica ddNTP primer extension. Las predicciones del efecto funcional de los SNP se realizaron con FuncPred. Resultados:La distribución del genotipo de todos los polimorfismos no se desvió significativamente del equilibrio de Hardy-Weinberg. Se observaron frecuencias significativamente mayores en polimorfismos de IL-1?, IFN-? e IL-10 en el grupo OT. Un polimorfismo en el promotor del gen IL-10 (-1082G / A) fue significativamente más prevalente en pacientes OT que en los controles (P = 1.93e-08; OR = 5.27e + 03; IC 95% = 3.18-8.739; pBONF = 3.48e-07). En contraste, el haplotipo AG del polimorfismo promotor del gen IL-10 (rs1800896, rs1800871) estuvo presente con menor frecuencia en pacientes con OT [P = 7e-04, OR (IC 95%) 0.10 (0.03-0.35)]. El polimorfismo (+ 874 A / T) de IFN-? se asoció con OT (P = 3.37e-05; OR = 4.2; IC 95% = 2.478-7.12; pBONF = 6.07e-04). El haplotipo GAG de los polimorfismos del promotor del gen IL-1? (rs1143634, rs1143627, rs16944), Conclusión: Los polimorfismos de IL-10, IFN-? e IL-1? influyen en el desarrollo de OT en la población colombiana. Nuestro estudio proporciona evidencia de que las variantes genéticas comunes en los genes Th1 (IL-1, IFN-?, TNF-?) y Th2 (IL10) están asociadas con el riesgo de desarrollar OT en pacientes de Colombia.Background: Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii which has the capacity to infect all warm-blooded animals worldwide. It is estimated that 30-70% of the human population is infected with this parasite, and essentially the entire human population is at risk of infection. A limited number of people develop symptoms, suggesting that host susceptibility and strain disparity can play a role in the variability of clinical symptoms. Toxoplasmosis is a major cause of visual defects in the Colombian population, however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. Methods & Materials: This work evaluates the associations between polymorphisms in genes coding for cytokines TNF-? (rs1799964, rs1800629, rs1799724, rs1800630, rs361525); IL-1? (rs16944, rs1143634, rs1143627), IL-1? (rs1800587); IFN-? (rs2430561); IL-10 (rs1800896, rs1800871), and the presence of ocular toxoplasmosis (OT) in a sample of Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the “ddNTP primer extension” technique. Functional effect predictions of SNPs were done using FuncPred. Results: Genotype distribution of all polymorphisms did not deviate significantly from the Hardy-Weinberg equilibrium. Significant higher frequencies in IL-1?, IFN-? and IL-10 polymorphisms were observed in the OT group. A polymorphism in the IL-10 gene-promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P?=?1.93e-08; OR?=?5.27e?+?03; 95%CI?=?3.18-8.739; pBONF?=?3.48e-07). In contrast, the haplotype “AG” of the IL-10 gene promoter polymorphism (rs1800896, rs1800871) was present with lower frequency in OT patients [P?=?7e-04, OR (95%CI) 0.10 (0.03-0.35)]. The polymorphism (+ 874 A/T) of IFN-? was associated with OT (P?=?3.37e-05; OR?=?4.2; 95%CI?=?2.478-7.12; pBONF?=?6.07e-04). The haplotype “GAG” of the IL-1? gene promoter polymorphisms (rs1143634, rs1143627, rs16944), appeared to be significantly associated with OT (P?=?0.0494). Conclusion: The IL-10, IFN-? and IL-1? polymorphisms influence development of OT in the Colombian population. Our study provides evidence that common genetic variants in Th1 (IL-1, IFN-?, TNF-?) and Th2 (IL10) genes are associated with risk to develop OT in patients from Colombia