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1.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

2.
Nat Commun ; 10(1): 3347, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350409

RESUMO

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or "wet" form of AMD, no therapy is successful for the non-neovascular or "dry" form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.

3.
JAMA Neurol ; 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31180460

RESUMO

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. Design, Setting, and Participants: The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis. Results: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (ß = -0.08; P = .03) and its repressive transcription factor, FOXG1 (ß = 0.13; P = .003), and global cognition function (ß = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). Conclusions and Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.

4.
Epigenomics ; 11(7): 739-749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140863

RESUMO

Aim: Salivary miRNA can be easily accessible biomarkers of alcohol dependence (AD). Materials & methods: The miRNA transcriptome in the saliva of 56 African-Americans (AAs; 28 AD patients/28 controls) and 64 European-Americans (EAs; 32 AD patients/32 controls) was profiled using small RNA sequencing. Differentially expressed miRNAs were identified. Salivary miRNAs were used to predict the AD presence using machine learning with Random Forests. Results: Seven miRNAs were differentially expressed in AA AD patients, and five miRNAs were differentially expressed in EA AD patients. The AD prediction accuracy based on top five miRNAs (ranked by Gini index) was 79.1 and 72.2% in AAs and EAs, respectively. Conclusion: This study provided the first evidence that salivary miRNAs are AD biomarkers.

5.
Aging Cell ; 18(4): e12964, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31144443

RESUMO

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10-8 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10-308 ), five windows at BIN1 (top p = 1.3 × 10-13 ), two windows at MS4A6A (top p = 2.7 × 10-10 ), two windows near MS4A4A (top p = 6.4 × 10-10 ), and one window at PICALM (p = 6.3 × 10-9 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10-10 ), brain DNA methylation (p = 2.15 × 10-10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10-4 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.

6.
Invest Ophthalmol Vis Sci ; 60(4): 1204-1212, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924847

RESUMO

Purpose: Current understanding of local disease pathophysiology in AMD is limited. Analysis of the human disease-affected tissue is most informative, as gene expression, expressed quantitative trait loci, microenvironmental, and epigenetic changes can be tissue, cell type, and location specific. Development of a novel translational treatment and prevention strategies particularly for earlier forms of AMD are needed, although access to human ocular tissue analysis is challenging. We present a standardized protocol to study rapidly processed postmortem donor eyes for molecular biochemical and genomic studies. Methods: We partnered with the Utah Lions Eye Bank to obtain donor human eyes, blood, and vitreous, within 6 hours postmortem. Phenotypic analysis was performed using spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. Macular and extramacular tissues were immediately isolated, and the neural retina and retinal pigment epithelium/choroid from each specimen were separated and preserved. Ocular disease phenotype was analyzed using clinically relevant grading criteria by a group of four ophthalmologists incorporating data from SD-OCT retinal images, fundus photographs, and medical records. Results: The use of multimodal imaging leads to greater resolution of retinal pathology, allowing greater phenotypic rigor for both interobserver phenotype and known clinical diagnoses. Further, our analysis resulted in excellent quality RNA, which demonstrated appropriate tissue segregation. Conclusions: The Utah protocol is a standardized methodology for analysis of disease mechanisms in AMD. It uniquely allows for simultaneous rigorous phenotypic, molecular biochemical, and genomic analysis of both systemic and local tissues. This better enables the development of disease biomarkers and therapeutic interventions.


Assuntos
Autopsia , Protocolos Clínicos , Olho/patologia , Degeneração Macular/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Fenômenos Bioquímicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biologia Molecular , Imagem Multimodal , Fenótipo , Fotografação , Estudos Retrospectivos , Doadores de Tecidos , Tomografia de Coerência Óptica/métodos , Utah
7.
JAMA Netw Open ; 2(3): e191350, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924900

RESUMO

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective: To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

8.
Semin Fetal Neonatal Med ; 24(2): 105-110, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30709700

RESUMO

Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure is a growing epidemic with significant variability in clinical presentation and severity. Currently, NAS severity cannot be predicted based on clinical factors alone. To date, small studies have identified genetic variants in opioid receptor and stress response genes that are associated with differences in NAS pharmacologic treatment rates and length of hospitalization. In addition, epigenetic variation in the mu opioid receptor (OPRM1) gene has been associated with differences in NAS hospitalization outcomes. Examination of maternal genetic and epigenetic profiles may assist in prediction of NAS severity. Large-scale genomic studies are needed to elucidate the genetic architecture of and epigenetic modification related to NAS in order to develop more tailored personalized treatments for NAS.

9.
Eur J Hum Genet ; 27(5): 811-823, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30683923

RESUMO

Complex diseases are usually associated with multiple correlated phenotypes, and the analysis of composite scores or disease status may not fully capture the complexity (or multidimensionality). Joint analysis of multiple disease-related phenotypes in genetic tests could potentially increase power to detect association of a disease with common SNPs (or genes). Gene-based tests are designed to identify genes containing multiple risk variants that individually are weakly associated with a univariate trait. We combined three multivariate association tests (O'Brien method, TATES, and MultiPhen) with two gene-based association tests (GATES and VEGAS) and compared performance (type I error and power) of six multivariate gene-based methods using simulated data. Data (n = 2000) for genetic sequence and correlated phenotypes were simulated by varying causal variant proportions and phenotype correlations for various scenarios. These simulations showed that two multivariate association tests (TATES and MultiPhen, but not O'Brien) paired with VEGAS have inflated type I error in all scenarios, while the three multivariate association tests paired with GATES have correct type I error. MultiPhen paired with GATES has higher power than competing methods if the correlations among phenotypes are low (r < 0.57). We applied these gene-based association methods to a GWAS dataset from the Alzheimer's Disease Genetics Consortium containing three neuropathological traits related to Alzheimer disease (neuritic plaque, neurofibrillary tangles, and cerebral amyloid angiopathy) measured in 3500 autopsied brains. Gene-level significant evidence (P < 2.7 × 10-6) was identified in a region containing three contiguous genes (TRAPPC12, TRAPPC12-AS1, ADI1) using O'Brien and VEGAS. Gene-wide significant associations were not observed in univariate gene-based tests.

10.
PLoS Genet ; 14(12): e1007791, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30517106

RESUMO

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

11.
Alzheimers Dement ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30503768

RESUMO

INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood. METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families. RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10-10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10-10). DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

12.
Acta Neuropathol Commun ; 6(1): 115, 2018 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-30390709

RESUMO

The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF = 0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF = 0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile = 0.42, 95% confidence interval [CI] 0.22-0.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.29-0.98, p = 0.043), and increased synaptic protein density (ß = 0.306, 95% CI 0.065-0.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.16-0.99, p = 0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.

13.
Acta Neuropathol ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413934

RESUMO

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

14.
Transl Psychiatry ; 8(1): 208, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287806

RESUMO

Smoking and major depression frequently co-occur, at least in part due to shared genetic risk. However, the nature of the shared genetic basis is poorly understood. To detect genetic risk variants for comorbid nicotine dependence (ND) and major depression (MD), we conducted genome-wide association study (GWAS) in two samples of African-American participants (Yale-Penn 1 and 2) using linear mixed model, followed by meta-analysis. 3724 nicotine-exposed subjects were analyzed: 2596 from Yale-Penn-1 and 1128 from Yale-Penn-2. Continuous measures (Fagerström Test for Nicotine Dependence (FTND) scores and DSM-IV MD criteria) rather than disorder status were used to maximize the power of the GWAS. Genotypes were ascertained using the Illumina HumanOmni1-Quad array (Yale-Penn-1 sample) or the Illumina HumanCore Exome array (Yale-Penn-2 sample), followed by imputation based on the 1000 Genomes reference panel. An intronic variant at the GRIA4 locus, rs68081839, was significantly associated with ND-MD comorbidity (ß = 0.69 [95% CI, 0.43-0.89], P = 1.53 × 10-8). GRIA4 encodes an AMPA-sensitive glutamate receptor that mediates fast excitatory synaptic transmission and neuroplasticity. Conditional analyses revealed that the association was explained jointly by both traits. Enrichment analysis showed that the top risk genes and genes co-expressed with GRIA4 are enriched in cell adhesion, calcium ion binding, and synapses. They also have enriched expression in the brain and they have been implicated in the risk for other neuropsychiatric disorders. Further research is needed to determine the replicability of these findings and to identify the biological mechanisms through which genetic risk for each condition is conveyed.

15.
BMC Proc ; 12(Suppl 9): 44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275893

RESUMO

Background: The study of DNA methylation quantitative trait loci (meQTLs) helps dissect regulatory mechanisms underlying genetic associations of human diseases. In this study, we conducted the first genome-wide examination of genetic drivers of methylation variation in response to a triglyceride-lowering treatment with fenofibrate (response-meQTL) by using an efficient analytic approach. Methods: Subjects (n = 429) from the GAW20 real data set with genotype and both pre- (visit 2) and post- (visit 4) fenofibrate treatment methylation measurements were included. Following the quality control steps of removing certain cytosine-phosphate-guanine (CpG) probes, the post-/premethylation changes (post/pre) were log transformed and the association was performed on 208,449 CpG sites. An additive linear mixed-effects model was used to test the association between each CpG probe and single nucleotide polymorphisms (SNPs) around ±1 Mb region, with age, sex, smoke, batch effect, and principal components included as covariates. Bonferroni correction was applied to define the significance threshold (p < 5.6 × 10- 10, given a total of 89,217,303 tests). Finally, we integrated our response-meQTL (re-meQTL) findings with the published genome-wide association study (GWAS) catalog of human diseases/traits. Results: We identified 1087 SNPs as cis re-meQTLs associated with 610 CpG probes/sites located in 351 unique gene loci. Among these 1087 cis re-meQTL SNPs, 229 were unique and 6 were co-localized at 8 unique disease/trait loci reported in the GWAS catalog (enrichment p = 1.51 × 10- 23). Specifically, a lipid SNP, rs10903129, located in intron regions of gene TMEM57, was a re-meQTL (p = 3.12 × 10- 36) associated with the CpG probe cg09222892, which is in the upstream region of the gene RHCE, indicating a new target gene for rs10903129. In addition, we found that SNP rs12710728 has a suggestive association with cg17097782 (p = 1.77 × 10- 4), and that this SNP is in high linkage disequilibrium (LD) (R2 > 0.8) with rs7443270, which was previously reported to be associated with fenofibrate response (p = 5.00 × 10- 6). Conclusions: By using a novel analytic approach, we efficiently identified thousands of cis re-meQTLs that provide a unique resource for further characterizing functional roles and gene targets of the SNPs that are most responsive to fenofibrate treatment. Our efficient analytic approach can be extended to large response quantitative trait locus studies with large sample sizes and multiple time points data.

16.
Alcohol Clin Exp Res ; 42(12): 2337-2348, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30252935

RESUMO

BACKGROUND: Efforts to promote the cessation of harmful alcohol use are hindered by the affective and physiological components of alcohol withdrawal (AW), which can include life-threatening seizures. Although previous studies of AW and relapse have highlighted the detrimental role of stress, little is known about genetic risk factors. METHODS: We conducted a genome-wide association study of AW symptom count in uniformly assessed subjects with histories of serious AW, followed by additional genotyping in independent AW subjects. RESULTS: The top association signal for AW severity was in sortilin family neurotrophin receptor gene SORCS2 on chromosome 4 (European American meta-analysis n = 1,478, p = 4.3 × 10-9 ). There were no genome-wide significant findings in African Americans (n = 1,231). Bioinformatic analyses were conducted using publicly available high-throughput transcriptomic and epigenomic data sets, showing that in humans SORCS2 is most highly expressed in the nervous system. The identified SORCS2 risk haplotype is predicted to disrupt a stress hormone-modulated regulatory element that has tissue-specific activity in human hippocampus. We used human neural lineage cells to demonstrate in vitro a causal relationship between stress hormone levels and SORCS2 expression, and show that SORCS2 levels in culture are increased upon ethanol exposure and withdrawal. CONCLUSIONS: Taken together, these findings indicate that the pathophysiology of withdrawal may involve the effects of stress hormones on neurotrophic factor signaling. Further investigation of these pathways could produce new approaches to managing the aversive consequences of abrupt alcohol cessation.

17.
Front Neurosci ; 12: 592, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210277

RESUMO

The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p<8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.

18.
Neurobiol Aging ; 72: 188.e3-188.e12, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30201328

RESUMO

Systematic epistasis analyses in multifactorial disorders are an important step to better characterize complex genetic risk structures. We conducted a hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility. We identified a statistical epistasis signal between the single nucleotide polymorphisms rs3733980 and rs7175766 that was associated with AD in males (genome-wide significant pBonferroni-corrected=0.0165). This signal pointed toward the genes WW and C2 domain containing 1, aka KIBRA; 5q34 and TLN2 (talin 2; 15q22.2). Gene-based meta-analysis in 3 independent consortium data sets confirmed the identified interaction: the most significant (pmeta-Bonferroni-corrected=9.02*10-3) was for the single nucleotide polymorphism pair rs1477307 and rs4077746. In functional studies, WW and C2 domain containing 1, aka KIBRA and TLN2 coexpressed in the temporal cortex brain tissue of AD subjects (ß=0.17, 95% CI 0.04 to 0.30, p=0.01); modulated Tau toxicity in Drosophila eye experiments; colocalized in brain tissue cells, N2a neuroblastoma, and HeLa cell lines; and coimmunoprecipitated both in brain tissue and HEK293 cells. Our finding points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.

19.
Am J Med Genet B Neuropsychiatr Genet ; 177(5): 511-519, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30134085

RESUMO

Cognitive flexibility is a critical component of executive function and is strongly influenced by genetic factors. We conducted a genome-wide association study of cognitive flexibility (as measured by perseverative errors on the Wisconsin Card Sorting Test) in two sets of African American (AA) and European American (EA) subjects (Yale-Penn-1: 1,411 AAs/949 EAs; Yale-Penn-2: 1,178 AAs/1,335 EAs). We examined the association of cognitive flexibility with genotyped or imputed SNPs across the genome. In AAs, two correlated common single nucleotide polymorphisms (SNPs) (rs7165213/rs35633795) in the downstream region of the noncoding gene LOC101927286 on chromosome 15 showed genome-wide significant (GWS) associations with cognitive flexibility (Yale-Penn-1: p = 6.0 × 10-9 /1.3 × 10-8 ; Yale-Penn-2: p = .029/.010; meta-analysis: p = 4.2 × 10-7 /1.0 × 10-7 ) in the same effect direction. In EAs, no GWS associations were observed. Enriched gene sets identified by Data-driven Expression-Prioritized Integration for Complex Traits (DEPICT) analysis of the top SNPs (pmeta-analysis < 10-5 ) included the signalosome and ubiquitin-specific peptidase 9, X-linked (USP9X) subnetwork in AAs, and abnormal frontal and occipital bone morphology in EAs. We also performed polygenic risk score (PRS) analysis to examine the genetic correlation of cognition-proxy phenotypes (general cognitive function, education attainment, childhood intelligence, and infant head circumference) and cognitive flexibility in EAs. The PRS derived from general cognitive function-associated SNPs was significantly associated with cognitive flexibility. Nongenetic factors (age, education, sex, and tobacco recency) also exerted significant effects on cognitive flexibility. Our study demonstrates that both genetic and nongenetic factors impact cognitive flexibility, and variants in genes involved in protein degradation and brain development may contribute to population variation in cognitive function.

20.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

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