RESUMEN
Exercise exerts a wide range of beneficial effects for healthy physiology1. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut-brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise.
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Eje Cerebro-Intestino , Dopamina , Ejercicio Físico , Microbioma Gastrointestinal , Motivación , Carrera , Animales , Ratones , Encéfalo/citología , Encéfalo/metabolismo , Dopamina/metabolismo , Endocannabinoides/antagonistas & inhibidores , Endocannabinoides/metabolismo , Células Receptoras Sensoriales/metabolismo , Eje Cerebro-Intestino/fisiología , Microbioma Gastrointestinal/fisiología , Ejercicio Físico/fisiología , Ejercicio Físico/psicología , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/psicología , Modelos Animales , Humanos , Estriado Ventral/citología , Estriado Ventral/metabolismo , Carrera/fisiología , Carrera/psicología , Recompensa , IndividualidadRESUMEN
Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.
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Reparación del ADN , ADN/metabolismo , Anemia de Fanconi/genética , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Proteína de Replicación A/metabolismo , Supervivencia Celular , Reactivos de Enlaces Cruzados , ADN Helicasas/metabolismo , Exodesoxirribonucleasas/metabolismo , Anemia de Fanconi/metabolismo , Femenino , Inestabilidad Genómica , Células HEK293 , Heterocigoto , Humanos , Lactante , Mutación , RecQ Helicasas/metabolismo , Helicasa del Síndrome de WernerRESUMEN
Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =â -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.
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Cámara Anterior/patología , Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Cerrado/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Cámara Anterior/metabolismo , Pueblo Asiatico , Glaucoma de Ángulo Cerrado/patología , Humanos , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Central corneal thickness (CCT) is a highly heritable trait. Genes that significantly influence CCT can be candidate genes for common disorders in which CCT has been implicated, such as primary open-angle glaucoma (POAG) and keratoconus. Because the genetic factors controlling CCT in different Asian populations are unclear, we have built on previous work conducted on Singaporean Indians and Malays and extended our hypothesis to individuals of Chinese descent. We have followed up on all suggestive signals of association with CCT (P < 10(-4)) from the previously reported meta-analysis comprising Indians and Malays in a sample of Chinese individuals (n= 2681). In the combined sample (n= 7711), strong evidence of association was observed at four novel loci: IBTK on chromosome 6q14.1; CHSY1 on chromosome 15q26.3; and intergenic regions on chromosomes 7q11.2 and 9p23 (8.01 × 10(-11) < λ(GC) corrected P(meta) < 8.72 × 10(-8)). These four new loci explain an additional 4.3% of the total CCT variance across the sample cohorts over and above that of previously identified loci. We also extend on a previous finding at a fifth locus (AKAP13) where a new single-nucleotide polymorphism (rs1821481, P(meta) = 9.99 × 10(-9)) was found to be significantly more informative compared with the previously reported rs6496932 (P(meta) = 3.64 × 10(-5)). Performing association analysis in Asians may lead to the discovery of ethnic-specific genes that control CCT, offering further mechanistic insights into the regulation of CCT. In addition, it may also provide several candidate genes for interrogation for POAG, keratoconus and possible racial/ethnic variations.
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Córnea/patología , Etnicidad/genética , Mutación , Asia , Mapeo Cromosómico , Estudios de Cohortes , Glaucoma de Ángulo Abierto/genética , HumanosRESUMEN
Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratioâ=â1.26 (95% CI: 1.16-1.36), P(meta)â=â7.87×10(-9)) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.
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Astigmatismo/genética , Enfermedades de la Córnea/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Errores de Refracción/genética , Adulto , Anciano , Anciano de 80 o más Años , Asia , Astigmatismo/patología , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Enfermedades de la Córnea/patología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Errores de Refracción/patologíaRESUMEN
Central corneal thickness (CCT) is a risk factor of glaucoma, the most common cause of irreversible blindness worldwide. The identification of genetic determinants affecting CCT in the normal population will provide insights into the mechanisms underlying the association between CCT and glaucoma, as well as the pathogenesis of glaucoma itself. We conducted two genome-wide association studies for CCT in 5080 individuals drawn from two ethnic populations in Singapore (2538 Indian and 2542 Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067, p(meta) = 5.40 × 10⻹³, interval of RXRA-COL5A1 rs1536478, p(meta) = 3.05 × 10â»9). We confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469) [rs9938149 (p(meta) = 1.63 × 10⻹6) and rs12447690 (p(meta) = 1.92 × 10⻹4)]. Evidence of association exceeding the formal threshold for genome-wide significance was observed at rs7044529, an SNP located within COL5A1 when data from this study (n = 5080, P = 0.0012) were considered together with all published data (reflecting an additional 7349 individuals, p(Fisher) = 1.5 × 10â»9). These findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma.
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Pueblo Asiatico/genética , Colágeno/genética , Córnea/patología , Estudio de Asociación del Genoma Completo , Glaucoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Colágeno Tipo VIII/genética , Femenino , Glaucoma/etnología , Humanos , Malasia , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Factores de Riesgo , SingapurRESUMEN
Damage to the optic nerve (e.g. from glaucoma) has an adverse and often irreversible impact on vision. Earlier studies have suggested that the size of the optic nerve head could be governed by hereditary factors. We conducted a genome-wide association study (GWAS) on 4445 Singaporean individuals (n = 2132 of Indian and n = 2313 of Malay ancestry, respectively), with replication in Rotterdam, the Netherlands (n = 9326 individuals of Caucasian ancestry) using the most widely reported parameter for optic disc traits, the optic disc area. We identified a novel locus on chromosome 22q13.1, CARD10, which strongly associates with optic disc area in both Singaporean cohorts as well as in the Rotterdam Study (RS; rs9607469, per-allele change in optic disc area = 0.051 mm(2); P(meta) = 2.73×10(-12)) and confirmed the association between CDC7/TGFBR3 (lead single nucleotide polymorphism (SNP) rs1192415, P(meta) = 7.57×10(-17)) and ATOH7 (lead SNP rs7916697, P(meta) = 2.00 × 10(-15)) and optic disc area in Asians. This is the first Asian-based GWAS on optic disc area, identifying a novel locus for the optic disc area, but also confirming the results found in Caucasian persons suggesting that there are general genetic determinants applicable to the size of the optic disc across different ethnicities.
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Pueblo Asiatico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas Adaptadoras de Señalización CARD/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Glaucoma/genética , Disco Óptico/química , Proteoglicanos/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Adulto , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas Adaptadoras de Señalización CARD/metabolismo , Cromosomas Humanos Par 22/genética , Estudios de Cohortes , Femenino , Glaucoma/etnología , Humanos , Masculino , Persona de Mediana Edad , Disco Óptico/metabolismo , Polimorfismo de Nucleótido Simple , Proteoglicanos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismoRESUMEN
Outbred laboratory mice (Mus musculus) are readily available and have high fecundity, making them a popular choice in biomedical research, especially toxicological and pharmacological applications. Direct high throughput genome sequencing (HTS) of these widely used research animals is an important genetic quality control measure that enhances research reproducibility. HTS data have been used to confirm the common origin of outbred stocks and to molecularly define distinct outbred populations. But these data have also revealed unexpected population structure and homozygosity in some populations; genetic features that emerge when outbred stocks are not properly maintained. We used exome sequencing to discover and interrogate protein-coding variation in a newly established population of Swiss-derived outbred stock (J:ARC) that is closely related to other, commonly used CD-1 outbred populations. We used these data to describe the genetic architecture of the J:ARC population including heterozygosity, minor allele frequency, LD decay, and we defined novel, protein-coding sequence variation. These data reveal the expected genetic architecture for a properly maintained outbred stock and provide a basis for the on-going genetic quality control. We also compared these data to protein-coding variation found in a multiparent outbred stock, the Diversity Outbred (J:DO). We found that the more recently derived, multiparent outbred stock has significantly higher interindividual variability, greater overall genetic variation, higher heterozygosity, and fewer novel variants than the Swiss-derived J:ARC stock. However, among the novel variants found in the J:DO stock, significantly more are predicted to be protein-damaging. The fact that individuals from this population can tolerate a higher load of potentially damaging variants highlights the buffering effects of allelic diversity and the differing selective pressures in these stocks. While both outbred stocks offer significant individual heterozygosity, our data provide a molecular basis for their intended applications, where the J:DO are best suited for studies requiring maximum, population-level genetic diversity and power for mapping, while the J:ARC are best suited as a general-purpose outbred stock with robust fecundity, relatively low allelic diversity, and less potential for extreme phenotypic variability.
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Variación Genética , Ratones , Animales , Reproducibilidad de los Resultados , Frecuencia de los Genes , Heterocigoto , Homocigoto , AlelosRESUMEN
Physical activity is influenced by genetic factors whose expression may change with age. We employed an extension to the classical twin model that allows a modifier variable, age, to interact with the effects of the latent genetic and environmental factors. The model was applied to self-reported data from twins aged 19 to 50 from seven countries that collaborated in the GenomEUtwin project: Australia, Denmark, Finland, Norway, Netherlands, Sweden and United Kingdom. Results confirmed the importance of genetic influences on physical activity in all countries and showed an age-related decrease in heritability for 4 countries. In the other three countries age did not interact with heritability but those samples were smaller or had a more restricted age range. Effects of shared environment were absent, except in older Swedish participants. The study confirms the importance of taking age effects into account when exploring the genetic and environmental contribution to physical activity. It also suggests that the power of genome-wide association studies to identify the genetic variants contributing to physical activity may be larger in young adult cohorts.
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Comparación Transcultural , Actividad Motora , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto , Factores de Edad , Australia , Dinamarca , Ambiente , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Noruega , Autoinforme , Suecia , Reino Unido , Adulto JovenRESUMEN
The study of continuously varying, quantitative traits is important in evolutionary biology, agriculture, and medicine. Variation in such traits is attributable to many, possibly interacting, genes whose expression may be sensitive to the environment, which makes their dissection into underlying causative factors difficult. An important population parameter for quantitative traits is heritability, the proportion of total variance that is due to genetic factors. Response to artificial and natural selection and the degree of resemblance between relatives are all a function of this parameter. Following the classic paper by R. A. Fisher in 1918, the estimation of additive and dominance genetic variance and heritability in populations is based upon the expected proportion of genes shared between different types of relatives, and explicit, often controversial and untestable models of genetic and non-genetic causes of family resemblance. With genome-wide coverage of genetic markers it is now possible to estimate such parameters solely within families using the actual degree of identity-by-descent sharing between relatives. Using genome scans on 4,401 quasi-independent sib pairs of which 3,375 pairs had phenotypes, we estimated the heritability of height from empirical genome-wide identity-by-descent sharing, which varied from 0.374 to 0.617 (mean 0.498, standard deviation 0.036). The variance in identity-by-descent sharing per chromosome and per genome was consistent with theory. The maximum likelihood estimate of the heritability for height was 0.80 with no evidence for non-genetic causes of sib resemblance, consistent with results from independent twin and family studies but using an entirely separate source of information. Our application shows that it is feasible to estimate genetic variance solely from within-family segregation and provides an independent validation of previously untestable assumptions. Given sufficient data, our new paradigm will allow the estimation of genetic variation for disease susceptibility and quantitative traits that is free from confounding with non-genetic factors and will allow partitioning of genetic variation into additive and non-additive components.
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Estatura , Modelos Genéticos , Mapeo Cromosómico , Salud de la Familia , Marcadores Genéticos , Variación Genética , Genoma , Humanos , Funciones de Verosimilitud , Modelos Estadísticos , Fenotipo , HermanosRESUMEN
Most information in linkage analysis for quantitative traits comes from pairs of relatives that are phenotypically most discordant or concordant. Confounding this, within-family outliers from non-genetic causes may create false positives and negatives. We investigated the influence of within-family outliers empirically, using one of the largest genome-wide linkage scans for height. The subjects were drawn from Australian twin cohorts consisting of 8447 individuals in 2861 families, providing a total of 5815 possible pairs of siblings in sibships. A variance component linkage analysis was performed, either including or excluding the within-family outliers. Using the entire dataset, the largest LOD scores were on chromosome 15q (LOD 2.3) and 11q (1.5). Excluding within-family outliers increased the LOD score for most regions, but the LOD score on chromosome 15 decreased from 2.3 to 1.2, suggesting that the outliers may create false negatives and false positives, although rare alleles of large effect may also be an explanation. Several regions suggestive of linkage to height were found after removing the outliers, including 1q23.1 (2.0), 3q22.1 (1.9) and 5q32 (2.3). We conclude that the investigation of the effect of within-family outliers, which is usually neglected, should be a standard quality control measure in linkage analysis for complex traits and may reduce the noise for the search of common variants of modest effect size as well as help identify rare variants of large effect and clinical significance. We suggest that the effect of within-family outliers deserves further investigation via theoretical and simulation studies.
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Alelos , Estatura/genética , Ambiente , Escala de Lod , Hermanos , Adolescente , Adulto , Mapeo Cromosómico , Cromosomas Humanos , Femenino , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite , Sitios de Carácter Cuantitativo , GemelosRESUMEN
Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.
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Ayuno/sangre , Factor I del Crecimiento Similar a la Insulina/genética , Insulina/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Femenino , Humanos , Insulina/sangre , Masculino , Persona de Mediana EdadRESUMEN
Genes involved in pathways regulating body weight may operate differently in men and women. To determine whether sex-limited genes influence the obesity-related phenotype body mass index (BMI), we have conducted a general nonscalar sex-limited genome-wide linkage scan using variance components analysis in Mx (Neale, 2002). BMI measurements and genotypic data were available for 2053 Australian female and male adult twins and their siblings from 933 families. Clinical measures of BMI were available for 64.4% of these individuals, while only self-reported measures were available for the remaining participants. The mean age of participants was 39.0 years of age (SD 12.1 years). The use of a sex-limited linkage model identified areas on the genome where quantitative trait loci (QTL) effects differ between the sexes, particularly on chromosome 8 and 20, providing us with evidence that some of the genes responsible for BMI may have different effects in men and women. Our highest linkage peak was observed at 12q24 (-log10p = 3.02), which was near the recommended threshold for suggestive linkage (-log10p = 3.13). Previous studies have found evidence for a quantitative trait locus on 12q24 affecting BMI in a wide range of populations, and candidate genes for noninsulin-dependent diabetes mellitus, a consequence of obesity, have also been mapped to this region. We also identified many peaks near a -log10p of 2 (threshold for replicating an existing finding) in many areas across the genome that are within regions previously identified by other studies, as well as in locations that harbor genes known to influence weight regulation.
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Índice de Masa Corporal , Cromosomas Humanos/genética , Ligamiento Genético , Genoma Humano/genética , Sitios de Carácter Cuantitativo/genética , Gemelos/genética , Diabetes Mellitus Tipo 2/genética , Humanos , Masculino , Obesidad/genética , Factores SexualesAsunto(s)
Índice de Masa Corporal , Variación Genética , Proteínas de Unión al GTP Heterotriméricas/genética , Paridad/genética , Australia , Composición Corporal/genética , Femenino , Humanos , Periodo Posparto , Embarazo , Sistema de Registros , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genéticaRESUMEN
PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci. METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study. RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05×10(-8) and P=6.36×10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing. CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.
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ADN/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Adulto , Anciano , Anciano de 80 o más Años , Factor H de Complemento/genética , Factor H de Complemento/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Degeneración Macular/etnología , Degeneración Macular/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Estudios Prospectivos , Proteínas/metabolismo , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
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Envejecimiento/genética , Glucemia/metabolismo , Cromosomas Humanos Par 11/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Variación Genética , Factores de Intercambio de Guanina Nucleótido/genética , Cardiopatías/genética , Insulina/sangre , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Ayuno/sangre , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genómica , Cardiopatías/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak Pâ=â1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (Pâ=â4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; Pâ=â1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; Pâ=â8.9×10(-6)) and upstream of GLI2 (rs6721654; Pâ=â6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; Pâ=â3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
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Factor H de Complemento/genética , Estudio de Asociación del Genoma Completo , Degeneración Macular/genética , Proteínas/genética , Apolipoproteínas E/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Proteína Gli3 con Dedos de ZincRESUMEN
Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
Asunto(s)
Córnea/anatomía & histología , Fibronectinas/genética , Factores de Transcripción Forkhead/genética , Sitios Genéticos/genética , Queratocono/genética , Pueblo Asiatico/genética , Paquimetría Corneal , Proteína Forkhead Box O1 , Estudio de Asociación del Genoma Completo , Glaucoma/genética , Humanos , Análisis por Micromatrices , Oportunidad Relativa , Reacción en Cadena en Tiempo Real de la Polimerasa , Población Blanca/genéticaRESUMEN
Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
Asunto(s)
Biomarcadores/metabolismo , Sitios Genéticos/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Metaanálisis como Asunto , Factores de RiesgoRESUMEN
PURPOSE: To evaluate the association of genetic variants at chromosomes 8p21 and 4q12 with the risk of developing AMD and its two main subtypes, choroidal neovascular membrane (CNV) and polypoidal choroidal vasculopathy (PCV), in Asian populations. METHODS: The study population comprised 2360 patients with neovascular AMD (1013 typical AMD-CNV and 1282 PCV), and 3598 controls from four independent cohorts, two of Japanese (n = 4859) and two of Chinese (n = 1099) ethnicity. We performed a meta-analysis in case-control studies of two reported single nucleotide polymorphisms (SNPs) (rs13278062 at TNFRSF10A-LOC389641 on 8p21 and rs1713985 at REST-C4orf14-POLR2B-IGFBP7 on 4q12) by using logistic regression analysis adjusted for age and sex. Subgroup analysis by CNV and PCV subtypes were performed to evaluate the significance of these two variants. RESULTS: The reported association between rs13278062 at 8p21 and neovascular AMD was replicated in this population (P = 1.12 × 10(-4), odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.70-0.89). However, there was no association of rs1713985 at 4q12 with neovascular AMD, or its two subtypes, typical AMD-CNV and PCV (all P > 0.05). The study sample size had a statistical power of greater than 99% to detect an association of a risk allele with AMD with an OR of 1.30, as reported in the original study of rs1713985 and AMD. CONCLUSIONS: The present results did not replicate the reported association between rs1713985 at 4q12 and neovascular AMD. However, we confirmed the association between rs13278062 at 8p21 and neovascular AMD in Asian populations.