RESUMEN
Studying premortem DNA methylation from ancient DNA (aDNA) provides a proxy for ancient gene activity patterns, and hence valuable information on evolutionary changes in gene regulation. Due to statistical limitations, current methods to reconstruct aDNA methylation maps are constrained to high-coverage shotgun samples, which comprise a small minority of available ancient samples. Most samples are sequenced using in-situ hybridization capture sequencing which targets a predefined set of genomic positions. Here, we develop methods to reconstruct aDNA methylation maps of samples that were not sequenced using high-coverage shotgun sequencing, by way of pooling together individuals to obtain a DNA methylation map that is characteristic of a population. We show that the resulting DNA methylation maps capture meaningful biological information and allow for the detection of differential methylation across populations. We offer guidelines on how to carry out comparative studies involving ancient populations, and how to control the rate of falsely discovered differentially methylated regions. The ability to reconstruct DNA methylation maps of past populations allows for the development of a whole new frontier in paleoepigenetic research, tracing DNA methylation changes throughout human history, using data from thousands of ancient samples.
Asunto(s)
Metilación de ADN , ADN Antiguo , Humanos , Metilación de ADN/genética , Genoma , Genómica , Análisis de Secuencia de ADN/métodos , Genética HumanaRESUMEN
MOTIVATION: The rise in the number of genotyped ancient individuals provides an opportunity to estimate population admixture models for many populations. However, in models describing modern populations as mixtures of ancient ones, it is typically difficult to estimate the model mixing coefficients and to evaluate its fit to the data. RESULTS: We present LINADMIX, designed to tackle this problem by solving a constrained linear model when both the ancient and the modern genotypes are represented in a low-dimensional space. LINADMIX estimates the mixing coefficients and their standard errors, and computes a P-value for testing the model fit to the data. We quantified the performance of LINADMIX using an extensive set of simulated studies. We show that LINADMIX can accurately estimate admixture coefficients, and is robust to factors such as population size, genetic drift, proportion of missing data and various types of model misspecification. AVAILABILITY AND IMPLEMENTATION: LINADMIX is available as a python code at https://github.com/swidler/linadmix. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Asunto(s)
Programas Informáticos , Humanos , GenotipoRESUMEN
We report genome-wide DNA data for 73 individuals from five archaeological sites across the Bronze and Iron Ages Southern Levant. These individuals, who share the "Canaanite" material culture, can be modeled as descending from two sources: (1) earlier local Neolithic populations and (2) populations related to the Chalcolithic Zagros or the Bronze Age Caucasus. The non-local contribution increased over time, as evinced by three outliers who can be modeled as descendants of recent migrants. We show evidence that different "Canaanite" groups genetically resemble each other more than other populations. We find that Levant-related modern populations typically have substantial ancestry coming from populations related to the Chalcolithic Zagros and the Bronze Age Southern Levant. These groups also harbor ancestry from sources we cannot fully model with the available data, highlighting the critical role of post-Bronze-Age migrations into the region over the past 3,000 years.
Asunto(s)
ADN Antiguo/análisis , Etnicidad/genética , Flujo Génico/genética , Arqueología/métodos , ADN Mitocondrial/genética , Etnicidad/historia , Flujo Génico/fisiología , Variación Genética/genética , Genética de Población/métodos , Genoma Humano/genética , Genómica/métodos , Haplotipos , Historia Antigua , Migración Humana/historia , Humanos , Región Mediterránea , Medio Oriente , Análisis de Secuencia de ADNRESUMEN
Changes in potential regulatory elements are thought to be key drivers of phenotypic divergence. However, identifying changes to regulatory elements that underlie human-specific traits has proven very challenging. Here, we use 63 reconstructed and experimentally measured DNA methylation maps of ancient and present-day humans, as well as of six chimpanzees, to detect differentially methylated regions that likely emerged in modern humans after the split from Neanderthals and Denisovans. We show that genes associated with face and vocal tract anatomy went through particularly extensive methylation changes. Specifically, we identify widespread hypermethylation in a network of face- and voice-associated genes (SOX9, ACAN, COL2A1, NFIX and XYLT1). We propose that these repression patterns appeared after the split from Neanderthals and Denisovans, and that they might have played a key role in shaping the modern human face and vocal tract.
Asunto(s)
Metilación de ADN , ADN Antiguo , Cara/anatomía & histología , Fenotipo , Fonación/genética , Adulto , Anciano , Animales , Células Cultivadas , Niño , Condrocitos , Evolución Molecular , Femenino , Redes Reguladoras de Genes , Especiación Genética , Humanos , Laringe/anatomía & histología , Masculino , Persona de Mediana Edad , Hombre de Neandertal/genética , Pan troglodytes/genética , Cultivo Primario de Células , Lengua/anatomía & histología , Pliegues Vocales/anatomía & histología , Vocalización AnimalRESUMEN
Recombination events are not uniformly distributed and often cluster in narrow regions known as recombination hotspots. Several studies using different approaches have dramatically advanced our understanding of recombination hotspot regulation. Population genetic data have been used to map and quantify hotspots in the human genome. Genetic variation in recombination rates and hotspots usage have been explored in human pedigrees, mouse intercrosses, and by sperm typing. These studies pointed to the central role of the PRDM9 gene in hotspot modulation. In this study, we used single nucleotide polymorphisms (SNPs) from whole-genome resequencing and genotyping studies of mouse inbred strains to estimate recombination rates across the mouse genome and identified 47,068 historical hotspots--an average of over 2477 per chromosome. We show by simulation that inbred mouse strains can be used to identify positions of historical hotspots. Recombination hotspots were found to be enriched for the predicted binding sequences for different alleles of the PRDM9 protein. Recombination rates were on average lower near transcription start sites (TSS). Comparing the inferred historical recombination hotspots with the recent genome-wide mapping of double-strand breaks (DSBs) in mouse sperm revealed a significant overlap, especially toward the telomeres. Our results suggest that inbred strains can be used to characterize and study the dynamics of historical recombination hotspots. They also strengthen previous findings on mouse recombination hotspots, and specifically the impact of sequence variants in Prdm9.
Asunto(s)
Mapeo Cromosómico , Genoma/genética , Recombinación Genética/genética , Animales , Secuencia de Bases , Evolución Molecular , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Ratones , Motivos de Nucleótidos/genética , Regiones Promotoras Genéticas/genética , Especificidad de la EspecieRESUMEN
Because of their somatic cell origin, human induced pluripotent stem cells (HiPSCs) are assumed to carry a normal diploid genome, and adaptive chromosomal aberrations have not been fully evaluated. Here, we analyzed the chromosomal integrity of 66 HiPSC and 38 human embryonic stem cell (HESC) samples from 18 different studies by global gene expression meta-analysis. We report identification of a substantial number of cell lines carrying full and partial chromosomal aberrations, half of which were validated at the DNA level. Several aberrations resulted from culture adaptation, and others are suspected to originate from the parent somatic cell. Our classification revealed a third type of aneuploidy already evident in early passage HiPSCs, suggesting considerable selective pressure during the reprogramming process. The analysis indicated high incidence of chromosome 12 duplications, resulting in significant enrichment for cell cycle-related genes. Such aneuploidy may limit the differentiation capacity and increase the tumorigenicity of HiPSCs.
Asunto(s)
Aberraciones Cromosómicas , Células Madre Pluripotentes Inducidas , Aneuploidia , Aberraciones Cromosómicas/clasificación , Perfilación de la Expresión Génica , HumanosRESUMEN
Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca(2+) channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.
Asunto(s)
Canales de Calcio/genética , Neuralgia/genética , Animales , Canales de Calcio/metabolismo , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Ratones , Ratones Endogámicos , Fenotipo , Polimorfismo Genético , Sitios de Carácter Cuantitativo , Nervios Espinales/lesionesAsunto(s)
Trastorno Bipolar/genética , Moléculas de Adhesión Celular Neuronal/genética , Proteínas de la Matriz Extracelular/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Proteínas del Tejido Nervioso/genética , Trastornos Psicóticos/genética , Esquizofrenia/genética , Serina Endopeptidasas/genética , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Proteína ReelinaRESUMEN
Until last year, type 2 diabetes (T2D) susceptibility loci have hardly been identified, despite great effort. Recently, however, several whole-genome association (WGA) studies jointly uncovered 10 robustly replicated loci. Here, we examine these loci in the Ashkenazi Jewish (AJ) population in a sample of 1,131 cases versus 1,147 controls. Genetic predisposition to T2D in the AJ population was found similar to that established in the previous studies. One SNP, rs7754840 in the CDKAL1 gene, presented a significantly stronger effect in the AJ population as compared to the general Caucasian population. This may possibly be due to the increased homogeneity of the AJ population. The use of the SNPs considered in this study, to identify individuals at high (or low) risk to develop T2D, was found of limited value. Our study, however, strongly supports the robustness of WGA studies for the identification of genes affecting complex traits in general and T2D in particular.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Judíos/genética , Sitios de Carácter Cuantitativo , Estudios de Casos y Controles , Quinasa 5 Dependiente de la Ciclina/genética , Diabetes Mellitus Tipo 2/etnología , Frecuencia de los Genes , Genética de Población , Genotipo , Humanos , Israel , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Población Blanca/genética , ARNt MetiltransferasasRESUMEN
We give a unified treatment of the statistical foundations of population based association mapping and of family based linkage mapping of quantitative traits in humans. A central ingredient in the unification involves the efficient score statistic. The discussion focuses on generalized linear models with an additional illustration of the Cox (proportional hazards) model for age of onset data. We give analytic expressions for noncentrality parameters and show how they give qualitative insight into the loss of power that occurs if the scientist's assumed genetic model differs from nature's "true" genetic model. Issues to be studied in detail in the future development of this approach are discussed.
Asunto(s)
Mapeo Cromosómico , Interpretación Estadística de Datos , Modelos Genéticos , Sitios de Carácter Cuantitativo , Humanos , LinajeRESUMEN
Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation. The genome scan detected one previously reported quantitative trait locus (QTL) on chromosome 15 (pain1), but no additional QTLs were found. Interestingly, group caging introduced phenotypic noise large enough to completely mask the genetic effect of the chromosome 15 QTL. The reason appears to be that group-caging animals from the low-autotomy strain together with animals from the high-autotomy strain dramatically increases autotomy in the otherwise low-autotomy mice (males or females). The converse, suppression of pain behaviour in the high-autotomy strain when caged with the low-autotomy strain was also observed, but only in females. Even in isolated mice, the genetic effect of the chromosome 15 QTL was significant only in females. To determine why, we evaluated autotomy levels of females in 12 different inbred stains of mice and compared them to previously reported levels for males. Strikingly larger environmental variation was observed in males than in females for this pain phenotype. The high baseline variance in males can explain the difficulty in detecting the genetic effect, which was readily seen in females. Our study emphasizes the importance of sex and environment in the genetic analysis of pain.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Genoma/genética , Enfermedades del Sistema Nervioso Periférico/genética , Sitios de Carácter Cuantitativo/genética , Caracteres Sexuales , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Ambiente , Ambiente Controlado , Femenino , Vivienda para Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Fenotipo , Automutilación/genética , Automutilación/fisiopatología , Conducta Social , Especificidad de la EspecieRESUMEN
In a hidden Markov model, one "estimates" the state of the hidden Markov chain at t by computing via the forwards-backwards algorithm the conditional distribution of the state vector given the observed data. The covariance matrix of this conditional distribution measures the information lost by failure to observe directly the state of the hidden process. In the case where changes of state occur slowly relative to the speed at which information about the underlying state accumulates in the observed data, we compute approximately these covariances in terms of functionals of Brownian motion that arise in change-point analysis. Applications in gene mapping, where these covariances play a role in standardizing the score statistic and in evaluating the loss of noncentrality due to incomplete information, are discussed. Numerical examples illustrate the range of validity and limitations of our results.
Asunto(s)
Cadenas de Markov , Modelos Genéticos , Teoría de la ProbabilidadRESUMEN
Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Frecuencia de los Genes , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras del Transporte Vesicular , Estudios de Casos y Controles , Inglaterra , Femenino , Finlandia , Predisposición Genética a la Enfermedad , Genoma Humano , Alemania , Humanos , Israel , Judíos/genética , Masculino , Población BlancaRESUMEN
Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22 , Proteínas de la Membrana/genética , Esquizofrenia/genética , Alelos , Animales , Antipsicóticos/farmacología , Encéfalo/metabolismo , Estudios de Casos y Controles , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Estudios de Cohortes , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Humanos , Judíos/genética , Desequilibrio de Ligamiento , Masculino , Glicoproteínas de Membrana , Proteínas de la Membrana/metabolismo , Complejo GPIb-IX de Glicoproteína Plaquetaria , Polimorfismo de Nucleótido Simple , RatasRESUMEN
Crohn's disease (CD) is caused by a combination of environmental and genetic factors. It is not clear at present whether age of onset (AOO) is a random event or dictated by genotype or environmental factors. Mutations in the NOD2/caspase recruitment domains 15 (CARD15) and in the Toll-like receptor 4 (TLR4) gene have been associated with increased susceptibility for CD. We sought to determine whether single or multiple mutations in these genes are linked to earlier susceptibility for CD. A cohort of 189 patients with CD (82 pediatric onset, 107 adult onset) were genotyped for three disease-associated single-nucleotide polymorphisms (SNPs), one haplotype association (JW1-SNP5), and one background polymorphism (P268S) of the NOD2/CARD15 gene and for two SNPs of TLR4. Analysis of heterozygosity, homozygosity, alleles, and haplotypes of cohort on age or pediatric onset was performed. AOO ranged from 8 mo to 68 y. The presence of the three NOD2/CARD15 and two TLR4 mutations, the NOD2/CARD15 JW haplotype, compound heterozygosity, and homozygosity were not associated with AOO. Presence of P268S in the absence of known NOD2/CARD15 mutations was correlated with increasing age and adult onset of CD, whereas pediatric-onset disease was associated with male gender and the wild-type NOD2/CARD15 haplotype. Mutations in NOD2/CARD15 and TLR4 are not significantly associated with AOO in our population. Mutations that are not in linkage disequilibrium with the background mutation P268S of the NOD2/CARD15 gene probably play a more significant role in pediatric-onset disease.
Asunto(s)
Edad de Inicio , Enfermedad de Crohn/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Receptor Toll-Like 4/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Estudios de Cohortes , Enfermedad de Crohn/enzimología , Enfermedad de Crohn/metabolismo , Cartilla de ADN , Haplotipos , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteína Adaptadora de Señalización NOD2 , Receptor Toll-Like 4/metabolismoRESUMEN
We have produced a backcross (BC) population of 267 mice from the parental strains C3H/HeN and C58/J. The mice were phenotyped for neuropathic pain using the neuroma model. Subsequently all BC mice were genotyped in a region of chromosome 15 that has been previously suggested to contain a quantitative trait locus (QTL) for this trait. We have confirmed the linkage of the QTL, named pain1, to the central region of chromosome 15. Our finding provides the necessary robustness to justify efforts towards identification of the underlying gene.
Asunto(s)
Cromosomas , Predisposición Genética a la Enfermedad , Endogamia , Proteínas de la Membrana/genética , Dolor/genética , Sitios de Carácter Cuantitativo/genética , Animales , Mapeo Cromosómico , Genotipo , Ratones , Ratones Endogámicos , FenotipoRESUMEN
OBJECTIVES: Delayed growth is common in pediatric Crohn's disease (CD). Multiple factors have been shown to affect growth in this situation, the most prominent being the presence and severity of inflammation and inadequate nutritional intake. Inflammation, anorexia, and weight loss are all manifestations of circulating TNF-alpha, which is elevated in CD. The ability to secrete TNF-alpha may be affected by polymorphisms in the TNF-alpha promoter. The aim of our study was to determine whether growth retardation and disease severity in pediatric onset CD are affected by TNF promoter genotype. METHODS: Genotyping for TNF-alpha and NOD2/CARD15 single nucleotide polymorphisms was performed in 87 patients with detailed growth records. Parameters including disease location and disease severity were recorded, and the effect of these polymorphisms on Z-scores for height and weight at disease onset and during follow-up were analyzed. RESULTS: Lower age of onset was linked to more height retardation, while the presence of colonic disease and the absence of ileal disease were more likely to predict the absence of growth retardation. The presence of two polymorphisms thought to decrease circulating TNF-alpha was associated with higher mean Z-scores for height and a trend toward less growth retardation. Two other polymorphisms were modestly associated with disease severity. CONCLUSION: Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.
Asunto(s)
Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/fisiopatología , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/fisiopatología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Factor de Necrosis Tumoral alfa/genética , Adenina , Adolescente , Niño , Estudios de Cohortes , Enfermedad de Crohn/genética , Citosina , Femenino , Genotipo , Guanina , Humanos , Masculino , Índice de Severidad de la Enfermedad , TiminaRESUMEN
OBJECTIVES: Studies suggest that pediatric onset of Crohn's disease (CD) may demonstrate more frequent upper intestinal and colonic location and in male gender, in comparison to adults. Variability in age of onset (AOO) and location of disease have not been adequately explained to date. NOD2/CARD15 is highly expressed in the ileum, while TNF-alpha expression is distributed throughout the gastrointestinal tract. We hypothesized that polymorphisms that affect TNF-alpha function may influence variability of disease location and AOO of CD. METHODS: We evaluated two CD cohorts based on AOO (pediatric and adult onset) and 100 ethnically matched healthy controls. Patients were evaluated for AOO, disease location, and genotyped for the presence of polymorphisms in NOD2/CARD15 and in the TNF-alpha promoter region. RESULTS: Early AOO was associated with male gender, upper intestinal involvement, and a polymorphism in the binding site for NF-kappaB (TNF-863A polymorphism). NOD2 mutations and TNF-863A polymorphism had equivalent but opposite effects on disease location, with a strong combined effect (p= 0.004 corrected for multiple testing). NOD2/CARD15 was associated with ileal involvement, while presence of TNF-863A was inversely associated with ileal disease (OR = 0.42, p= 0.008) and positively associated with isolated colitis (OR = 2.16, p= 0.008, OR = 2.12, p= 0.03 corrected) and familial disease (p= 0.004). CONCLUSIONS: Pediatric onset of CD in our population was associated with a frequent polymorphism in the binding site for NF-kappaB in TNF-alpha promoter but not to defined NOD2/CARD15 disease-associated mutations. This polymorphism is associated with colitis and familial disease. NOD2/CARD15 mutations and the TNF-863C/A polymorphism have equivalent but opposite effects on disease location. These findings may help explain differences in CD phenotype.
Asunto(s)
Colon/patología , Enfermedad de Crohn/genética , Polimorfismo Genético , Regiones Promotoras Genéticas/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Edad de Inicio , Niño , Enfermedad de Crohn/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.
Asunto(s)
Trastorno Bipolar/genética , Catecol O-Metiltransferasa/genética , Esquizofrenia/genética , Trastorno Bipolar/etiología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Judíos , Masculino , Epidemiología Molecular , Polimorfismo de Nucleótido Simple , Riesgo , Esquizofrenia/etiología , Factores SexualesRESUMEN
We studied the patterns of linkage disequilibrium (LD) in the human genome among three populations: African Americans, Caucasians and Ashkenazi Jews. These three populations represent admixed, outbred and isolated populations, respectively. The study examined defined chromosomal regions across the whole genome. We found that SNP allele frequencies are highly correlated between Ashkenazi Jews and Caucasians and somewhat distinct in African Americans. In addition, Ashkenazi Jews have a modest increase in LD compared with Caucasians, and both have greater LD than African Americans. The three populations differed more significantly with regard to haplotype heterogeneity. We found, as expected, that Ashkenazi Jews display the greatest extent of homogeneity and African Americans the greatest extent of heterogeneity. We found that most of the variance in LD can be attributed to the difference between regions and markers rather than to that between different population types. The average recombination rates estimated by low-resolution genetic maps can only explain a small fraction of the variance between regions. We found that LD (in terms of r(2)) decreases as a function of distance even within the so-called 'haplotype blocks'. This has significant consequences when using LD mapping for the genetic dissection of complex traits, as higher density SNP maps will be required to scan the genome.