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1.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

2.
Nat Hum Behav ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462475

RESUMO

Genome-wide association studies (GWAS) have identified several common genetic variants influencing major depression and general cognitive abilities, but little is known about whether the two share any of their genetic aetiology. Here we investigate shared genomic architectures between major depression (MD) and general intelligence (INT) with the MiXeR statistical tool and their overlapping susceptibility loci with conjunctional false discovery rate (conjFDR), which evaluate the level of overlap in genetic variants and improve the power for gene discovery between two phenotypes. We analysed GWAS data on MD (n = 480,359) and INT (n = 269,867) to characterize polygenic architecture and identify genetic loci shared between these phenotypes. Despite non-significant genetic correlation (rg = -0.0148, P = 0.50), we observed large polygenic overlap and identified 92 loci shared between MD and INT at conjFDR < 0.05. Among the shared loci, 69 and 64 are new for MD and INT, respectively. Our study demonstrates polygenic overlap between these phenotypes with a balanced mixture of effect.

3.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

4.
Acta Neuropathol Commun ; 8(1): 160, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912321

RESUMO

In the clinical diagnosis of dementia with Lewy bodies, distinction from Alzheimer's disease is suboptimal and complicated by shared genetic risk factors and frequent co-pathology. In the present study we tested the ability of polygenic scores for Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease to differentiate individuals in a 2713-participant, pathologically defined sample. A dementia with Lewy bodies polygenic score that excluded apolipoprotein E due to its overlap with Alzheimer's disease risk was specifically associated with at least limbic (transitional) Lewy-related pathology and a pathological diagnosis of dementia with Lewy bodies. An Alzheimer's disease polygenic score was associated with neuritic plaques and neurofibrillary tangles but not Lewy-related pathology, and was most strongly associated with an Alzheimer's pathological diagnosis. Our results indicate that an assessment of genetic risk may be useful to clinically distinguish between Alzheimer's disease and dementia with Lewy bodies. Notably, we found no association with a Parkinson's disease polygenic score, which aligns with evidence that dementia with Lewy bodies has a distinct genetic signature that can be exploited to improve clinical diagnoses.

5.
Environ Int ; 143: 105933, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32659528

RESUMO

BACKGROUND: Emerging findings have increased concern that exposure to fine particulate matter air pollution (aerodynamic diameter ≤ 2.5 µm; PM2.5) may be neurotoxic, even at lower levels of exposure. Yet, additional studies are needed to determine if exposure to current PM2.5 levels may be linked to hemispheric and regional patterns of brain development in children across the United States. OBJECTIVES: We examined the cross-sectional associations between geocoded measures of concurrent annual average outdoor PM2.5 exposure, regional- and hemisphere-specific differences in brain morphometry and cognition in 10,343 9- and 10- year-old children. METHODS: High-resolution structural T1-weighted brain magnetic resonance imaging (MRI) and NIH Toolbox measures of cognition were collected from children at ages 9-10 years. FreeSurfer was used to quantify cortical surface area, cortical thickness, as well as subcortical and cerebellum volumes in each hemisphere. PM2.5 concentrations were estimated using an ensemble-based model approach and assigned to each child's primary residential address collected at the study visit. We used mixed-effects models to examine regional- and hemispheric- effects of PM2.5 exposure on brain estimates and cognition after considering nesting of participants by familial relationships and study site, adjustment for socio-demographic factors and multiple comparisons. RESULTS: Annual residential PM2.5 exposure (7.63 ± 1.57 µg/m3) was associated with hemispheric specific differences in gray matter across cortical regions of the frontal, parietal, temporal and occipital lobes as well as subcortical and cerebellum brain regions. There were hemispheric-specific associations between PM2.5 exposures and cortical surface area in 9/31 regions; cortical thickness in 22/27 regions; and volumes of the thalamus, pallidum, and nucleus accumbens. We found neither significant associations between PM2.5 and task performance on individual measures of neurocognition nor evidence that sex moderated the observed associations. DISCUSSION: Even at relatively low-levels, current PM2.5 exposure across the U.S. may be an important environmental factor influencing patterns of structural brain development in childhood. Prospective follow-up of this cohort will help determine how current levels of PM2.5 exposure may affect brain development and subsequent risk for cognitive and emotional problems across adolescence.

6.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

7.
Biol Psychiatry ; 87(12): 1052-1062, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061372

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown. METHODS: We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment (N = 842,499), and general intelligence (N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations. The genetic variants identified were characterized in terms of function, expression, and biological processes. RESULTS: We identified 58 linkage disequilibrium-independent ADHD-associated loci (conditional FDR < 0.01), of which 30 were shared between ADHD and educational attainment or general intelligence (conjunctional FDR < 0.01) and 46 were novel risk loci for ADHD. CONCLUSIONS: These results expand on previous genetic and epidemiological studies and support the hypothesis of a shared genetic basis between these phenotypes. Although the clinical utility of the identified loci remains to be determined, they can be used as resources to guide future studies aiming to disentangle the complex etiologies of ADHD, educational attainment, and general intelligence.

8.
JAMA Psychiatry ; 77(5): 503-512, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913414

RESUMO

Importance: People with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown. Objective: To assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them. Design, Setting, and Participants: Using a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018. Main Outcomes and Measures: The primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways. Results: Genome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways. Conclusions and Relevance: In this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

9.
Mol Psychiatry ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792363

RESUMO

Differential diagnosis between childhood onset attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) remains a challenge, mainly due to overlapping symptoms and high rates of comorbidity. Despite this, genetic correlation reported for these disorders is low and non-significant. Here we aimed to better characterize the genetic architecture of these disorders utilizing recent large genome-wide association studies (GWAS). We analyzed independent GWAS summary statistics for ADHD (19,099 cases and 34,194 controls) and BD (20,352 cases and 31,358 controls) applying the conditional/conjunctional false discovery rate (condFDR/conjFDR) statistical framework that increases the power to detect novel phenotype-specific and shared loci by leveraging the combined power of two GWAS. We observed cross-trait polygenic enrichment for ADHD conditioned on associations with BD, and vice versa. Leveraging this enrichment, we identified 19 novel ADHD risk loci and 40 novel BD risk loci at condFDR <0.05. Further, we identified five loci jointly associated with ADHD and BD (conjFDR < 0.05). Interestingly, these five loci show concordant directions of effect for ADHD and BD. These results highlight a shared underlying genetic risk for ADHD and BD which may help to explain the high comorbidity rates and difficulties in differentiating between ADHD and BD in the clinic. Improving our understanding of the underlying genetic architecture of these disorders may aid in the development of novel stratification tools to help reduce these diagnostic difficulties.

10.
J Cardiovasc Comput Tomogr ; 13(4): 203-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31104941

RESUMO

BACKGROUND: Genetic risk scores (GRSs) have been associated with CHD events and coronary artery calcium (CAC). We sought to evaluate the ability of a GRS to improve CAC as a screening test. METHODS: Using the results of the most recent genome-wide association studies, we calculated a GRS in 6660 individuals from the Multi-Ethnic Study of Atherosclerosis and used it to determine the optimal age for an individual to undergo CAC screening. RESULTS: This 157-SNP GRS was predictive of non-zero CAC in individuals aged 44-54 and improved the positive yield of CAC as a screening test in this age group. The GRS was predictive of CAC in the entire multi-ethnic cohort and in each self-identified ethnic group (European American, Chinese American, African American, and Hispanic American) assessed individually. Given a specified target yield rate of non-zero CAC, an equation was derived to calculate an individual's optimal age to undergo CAC screening. In addition, a "direct-to-consumer" GRS consisting of only risk SNPs or their proxies that are directly genotyped on the 23andMe v5 chip (102-SNP GRS) was assessed in the European American population and was predictive of non-zero CAC in younger individuals. CONCLUSION: A GRS is associated with non-zero CAC in a multi-ethnic cohort and can be used to calculate the age of a person's first calcium scan, given a target threshold for CAC discovery. Furthermore, an inexpensive and widely available "direct-to-consumer" GRS was found to be a viable option to calculate the optimal age for CAC screening.


Assuntos
Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/genética , Testes Genéticos , Polimorfismo de Nucleotídeo Único , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tomada de Decisão Clínica , Doença da Artéria Coronariana/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , Calcificação Vascular/etnologia
11.
JAMA Neurol ; 75(7): 860-875, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29630712

RESUMO

Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results: Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; ß = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). Conclusions and Relevance: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder.


Assuntos
Doença de Alzheimer/genética , Esclerose Amiotrófica Lateral/genética , Demência Frontotemporal/genética , Doença de Parkinson/genética , Paralisia Supranuclear Progressiva/genética , Doenças dos Gânglios da Base/genética , Proteína C9orf72/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Superóxido Dismutase-1/genética , Proteinopatias TDP-43/genética , Proteínas de Transporte Vesicular/genética , Proteínas tau/genética
12.
Transl Psychiatry ; 8(1): 73, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29636460

RESUMO

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.


Assuntos
Predisposição Genética para Doença , Doenças Neurodegenerativas/genética , Receptores CXCR4/genética , Animais , Encéfalo/metabolismo , Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Camundongos Transgênicos , Microglia/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores CXCR4/metabolismo , Fatores de Risco
14.
PLoS Med ; 15(1): e1002487, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315334

RESUMO

BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal. CONCLUSIONS: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.


Assuntos
Demência Frontotemporal/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Idoso , Humanos , Pessoa de Meia-Idade
15.
JAMA Psychiatry ; 74(10): 1065-1075, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28746715

RESUMO

Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10-7), general cognitive function (z score, -4.43; P = 9.42 × 10-6), and verbal-numerical reasoning (z score, -5.43; P = 5.64 × 10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.


Assuntos
Disfunção Cognitiva , Esquizofrenia , Adulto , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Loci Gênicos , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Tempo de Reação , Esquizofrenia/complicações , Esquizofrenia/diagnóstico , Esquizofrenia/genética , alfa Catenina/genética
16.
Acta Neuropathol ; 133(5): 825-837, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28271184

RESUMO

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p < 2.0 × 10-16). Functionally, we found that these shared risk genes were associated with protein interaction and gene co-expression networks and showed enrichment for several neurodevelopmental pathways. Our findings suggest: (1) novel genetic overlap between CBD and PSP beyond the MAPT locus; (2) strong ties between CBD and FTD through the MAPT clade, and (3) unique combinations of overlapping genes that may, in part, influence selective regional or neuronal vulnerability observed in specific tauopathies.


Assuntos
Demência Frontotemporal/patologia , Neurônios/patologia , Paralisia Supranuclear Progressiva/patologia , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/patologia , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Humanos , Corpos de Inclusão/patologia , Fatores de Risco , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/genética , Tauopatias/patologia , Proteínas tau/metabolismo
17.
J Neurol Neurosurg Psychiatry ; 88(2): 152-164, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27899424

RESUMO

BACKGROUND: Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. METHODS: Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. RESULTS: We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3'-UTR=PVRL2, p=2.21×10-12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10-7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. CONCLUSIONS: Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.


Assuntos
Doença de Alzheimer/genética , Demência Frontotemporal/genética , Predisposição Genética para Doença , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudo de Associação Genômica Ampla , Genótipo , Humanos
18.
Ann Clin Transl Neurol ; 3(9): 668-77, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27648456

RESUMO

OBJECTIVE: The ε4 allele of apolipoprotein E (APOE) is the strongest known common genetic risk factor for Alzheimer's disease (AD) and alters age of onset in retrospective studies. Here, we longitudinally test the effects of APOE ε4 genotype and age during progression from normal cognition to AD. METHODS: Using data from 5381 cognitively normal older individuals and Cox proportional hazards models, we longitudinally tested the effects of APOE genotype on progression from normal cognition to mild cognitive impairment (MCI) or AD in four age strata (<60, 60-70, 70-80, 80 + ) and with a sliding window approach between ages 60 and 85. RESULTS: We found that APOE ε4 carrier status and dosage significantly influenced progression to MCI or AD in all four age groups and that APOE ε4-associated progression risk peaked between ages 70 and 75. We confirmed APOE ε4-associated progression risk in a subset of the cohort with pathologically proven diagnoses. INTERPRETATION: Our findings indicate that in clinically normal individuals, APOE ε4 status significantly predicts progression to MCI or AD across older adulthood and that this risk varies with age. This information will be useful as therapeutic interventions become available and clinical decisions can be individually tailored based on age and genetic data.

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