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1.
Transl Psychiatry ; 9(1): 283, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712607

RESUMO

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10-208, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10-17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10-5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

2.
Nat Commun ; 10(1): 3927, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

3.
Nat Rev Genet ; 20(10): 567-581, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31171865

RESUMO

The genetic correlation describes the genetic relationship between two traits and can contribute to a better understanding of the shared biological pathways and/or the causality relationships between them. The rarity of large family cohorts with recorded instances of two traits, particularly disease traits, has made it difficult to estimate genetic correlations using traditional epidemiological approaches. However, advances in genomic methodologies, such as genome-wide association studies, and widespread sharing of data now allow genetic correlations to be estimated for virtually any trait pair. Here, we review the definition, estimation, interpretation and uses of genetic correlations, with a focus on applications to human disease.

4.
Sci Rep ; 9(1): 5055, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911067

RESUMO

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 µM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease.

5.
Cell ; 177(1): 115-131, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901534

RESUMO

Identifying the causes of similarities and differences in genetic disease prevalence among humans is central to understanding disease etiology. While present-day humans are not strongly differentiated, vast amounts of genomic data now make it possible to study subtle patterns of genetic variation. This allows us to trace our genomic history thousands of years into the past and its implications for the distribution of disease-associated variants today. Genomic analyses have shown that demographic processes shaped the distribution and frequency of disease-associated variants over time. Furthermore, local adaptation to new environmental conditions-including pathogens-has generated strong patterns of differentiation at particular loci. Researchers are also beginning to uncover the genetic architecture of complex diseases, affected by many variants of small effect. The field of population genomics thus holds great potential for providing further insights into the evolution of human disease.

6.
Nat Neurosci ; 22(3): 353-361, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692689

RESUMO

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.


Assuntos
Encéfalo/embriologia , Regulação da Expressão Gênica , Predisposição Genética para Doença , Transtornos Mentais/genética , Encéfalo/metabolismo , Estudos de Coortes , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
Nat Commun ; 9(1): 5296, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30546018

RESUMO

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.


Assuntos
Meio Ambiente , Predisposição Genética para Doença/genética , Geografia , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Mapeamento Cromossômico/métodos , Dinamarca/epidemiologia , Humanos , Estudo de Prova de Conceito , Fatores de Risco
8.
Sci Rep ; 8(1): 12585, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135563

RESUMO

Higher cognitive functions are regarded as one of the main distinctive traits of humans. Evidence for the cognitive evolution of human beings is mainly based on fossil records of an expanding cranium and an increasing complexity of material culture artefacts. However, the molecular genetic factors involved in the evolution are still relatively unexplored. Here, we investigated whether genomic regions that underwent positive selection in humans after divergence from Neanderthals are enriched for genetic association with phenotypes related to cognitive functions. We used genome wide association data from a study of college completion (N = 111,114), one of educational attainment (N = 293,623) and two different studies of general cognitive ability (N = 269,867 and 53,949). We found nominally significant polygenic enrichment of associations with college completion (p = 0.025), educational attainment (p = 0.043) and general cognitive ability (p = 0.015 and 0.025, respectively), suggesting that variants influencing these phenotypes are more prevalent in evolutionarily salient regions. The enrichment remained significant after controlling for other known genetic enrichment factors, and for affiliation to genes highly expressed in the brain. These findings support the notion that phenotypes related to higher order cognitive skills typical of humans have a recent genetic component that originated after the separation of the human and Neanderthal lineages.

9.
Nat Genet ; 50(9): 1210-1211, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30158681
10.
Transl Psychiatry ; 8(1): 114, 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884845

RESUMO

Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William's Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e-5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e-4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

11.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 454-467, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29704319

RESUMO

Traditional genome-wide association studies (GWAS) have successfully detected genetic variants associated with schizophrenia. However, only a small fraction of heritability can be explained. Gene-set/pathway-based methods can overcome limitations arising from single nucleotide polymorphism (SNP)-based analysis, but most of them place constraints on size which may exclude highly specific and functional sets, like macromolecules. Voltage-gated calcium (Cav ) channels, belonging to macromolecules, are composed of several subunits whose encoding genes are located far away or even on different chromosomes. We combined information about such molecules with GWAS data to investigate how functional channels associated with schizophrenia. We defined a biologically meaningful SNP-set based on channel structure and performed an association study by using a validated method: SNP-set (sequence) kernel association test. We identified eight subtypes of Cav channels significantly associated with schizophrenia from a subsample of published data (N = 56,605), including the L-type channels (Cav 1.1, Cav 1.2, Cav 1.3), P-/Q-type Cav 2.1, N-type Cav 2.2, R-type Cav 2.3, T-type Cav 3.1, and Cav 3.3. Only genes from Cav 1.2 and Cav 3.3 have been implicated by the largest GWAS (N = 82,315). Each subtype of Cav channels showed relatively high chip heritability, proportional to the size of its constituent gene regions. The results suggest that abnormalities of Cav channels may play an important role in the pathophysiology of schizophrenia and these channels may represent appropriate drug targets for therapeutics. Analyzing subunit-encoding genes of a macromolecule in aggregate is a complementary way to identify more genetic variants of polygenic diseases. This study offers the potential of power for discovery the biological mechanisms of schizophrenia.

12.
Hum Mol Genet ; 27(R1): R22-R28, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29522091

RESUMO

Structural neuroimaging measures based on magnetic resonance imaging have been at the forefront of imaging genetics. Global efforts to ensure homogeneity of measurements across study sites have enabled large-scale imaging genetic projects, accumulating nearly 50K samples for genome-wide association studies (GWAS). However, not many novel genetic variants have been identified by these GWAS, despite the high heritability of structural neuroimaging measures. Here, we discuss the limitations of using heritability as a guidance for assessing statistical power of GWAS, and highlight the importance of discoverability-which is the power to detect genetic variants for a given phenotype depending on its unique genomic architecture and GWAS sample size. Further, we present newly developed methods that boost genetic discovery in imaging genetics. By redefining imaging measures independent of traditional anatomical conventions, it is possible to improve discoverability, enabling identification of more genetic effects. Moreover, by leveraging enrichment priors from genomic annotations and independent GWAS of pleiotropic traits, we can better characterize effect size distributions, and identify reliable and replicable loci associated with structural neuroimaging measures. Statistical tools leveraging novel insights into the genetic discoverability of human traits, promises to accelerate the identification of genetic underpinnings underlying brain structural variation.

13.
J Am Acad Child Adolesc Psychiatry ; 57(2): 86-95, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29413154

RESUMO

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric condition. By exploiting the reported relationship between ADHD and educational attainment (EA), we aimed to improve discovery of ADHD-associated genetic variants and to investigate genetic overlap between these phenotypes. METHOD: A conditional/conjunctional false discovery rate (condFDR/conjFDR) method was applied to genome-wide association study (GWAS) data on ADHD (2,064 trios, 896 cases, and 2,455 controls) and EA (n=328,917) to identify ADHD-associated loci and loci overlapping between ADHD and EA. Identified single nucleotide polymorphisms (SNPs) were tested for association in an independent population-based study of ADHD symptoms (n=17,666). Genetic correlation between ADHD and EA was estimated using LD score regression and Pearson correlation. RESULTS: At levels of condFDR<0.01 and conjFDR<0.05, we identified 5 ADHD-associated loci, 3 of these being shared between ADHD and EA. None of these loci had been identified in the primary ADHD GWAS, demonstrating the increased power provided by the condFDR/conjFDR analysis. Leading SNPs for 4 of 5 identified regions are in introns of protein coding genes (KDM4A, MEF2C, PINK1, RUNX1T1), whereas the remaining one is an intergenic SNP on chromosome 2 at 2p24. Consistent direction of effects in the independent study of ADHD symptoms was shown for 4 of 5 identified loci. A polygenic overlap between ADHD and EA was supported by significant genetic correlation (rg=-0.403, p=7.90×10-8) and >10-fold mutual enrichment of SNPs associated with both traits. CONCLUSION: We identified 5 novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and EA. These findings could aid understanding of the genetic risk architecture of ADHD and its relation to EA.

14.
Science ; 359(6376): 693-697, 2018 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-29439242

RESUMO

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.


Assuntos
Predisposição Genética para Doença , Transtornos Mentais/genética , Herança Multifatorial , Doenças do Sistema Nervoso/genética , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Polimorfismo de Nucleotídeo Único , Transcrição Genética
15.
Sci Rep ; 8(1): 674, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330379

RESUMO

Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Herança Multifatorial , Receptores Nicotínicos/genética
16.
Sci Rep ; 7(1): 11380, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28900119

RESUMO

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.

17.
JAMA Neurol ; 74(7): 780-792, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28586827

RESUMO

Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.


Assuntos
Doenças Autoimunes/genética , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Artrite Reumatoide/genética , Doença Celíaca/genética , Colite Ulcerativa/genética , Doença de Crohn/genética , Diabetes Mellitus Tipo 1/genética , Loci Gênicos , Humanos , Esclerose Múltipla/genética , Psoríase/genética , Fatores de Risco
18.
Nat Commun ; 8: 15539, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28537267

RESUMO

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10-8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.


Assuntos
Endometriose/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/metabolismo , Redes e Vias Metabólicas/genética , Adulto , Idoso , Endometriose/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
19.
PLoS Med ; 14(3): e1002258, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28323831

RESUMO

BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. CONCLUSIONS: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.


Assuntos
Doença de Alzheimer/epidemiologia , Apolipoproteínas E/genética , Avaliação Geriátrica/métodos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/metabolismo , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia
20.
PLoS One ; 12(1): e0169227, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28081145

RESUMO

Schizophrenia is suggested to be a by-product of the evolution in humans, a compromise for our language, creative thinking and cognitive abilities, and thus, essentially, a human disorder. The time of its origin during the course of human evolution remains unclear. Here we investigate several markers of early human evolution and their relationship to the genetic risk of schizophrenia. We tested the schizophrenia evolutionary hypothesis by analyzing genome-wide association studies of schizophrenia and other human phenotypes in a statistical framework suited for polygenic architectures. We analyzed evolutionary proxy measures: human accelerated regions, segmental duplications, and ohnologs, representing various time periods of human evolution for overlap with the human genomic loci associated with schizophrenia. Polygenic enrichment plots suggest a higher prevalence of schizophrenia associations in human accelerated regions, segmental duplications and ohnologs. However, the enrichment is mostly accounted for by linkage disequilibrium, especially with functional elements like introns and untranslated regions. Our results did not provide clear evidence that markers of early human evolution are more likely associated with schizophrenia. While SNPs associated with schizophrenia are enriched in HAR, Ohno and SD regions, the enrichment seems to be mediated by affiliation to known genomic enrichment categories. Taken together with previous results, these findings suggest that schizophrenia risk may have mainly developed more recently in human evolution.


Assuntos
Evolução Molecular , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Feminino , Marcadores Genéticos , Humanos , Masculino , Fatores de Risco
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