Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Hum Mol Genet ; 28(19): 3327-3338, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504550

RESUMEN

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.


Asunto(s)
Mapeo Cromosómico/métodos , Estudio de Asociación del Genoma Completo/métodos , Obesidad Infantil/genética , Polimorfismo de Nucleótido Simple , Tumor de Wilms/genética , Teorema de Bayes , Estudios de Casos y Controles , Niño , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino
2.
Hum Mol Genet ; 22(13): 2735-47, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23449627

RESUMEN

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.


Asunto(s)
Adiposidad/genética , Estatura/genética , Estudio de Asociación del Genoma Completo , Pubertad/genética , Sitios de Carácter Cuantitativo , Adolescente , Factores de Edad , Índice de Masa Corporal , Niño , Femenino , Estudios de Seguimiento , Expresión Génica , Ligamiento Genético , Humanos , Masculino , Menarquia , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fenotipo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven
3.
Commun Biol ; 7(1): 175, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38347176

RESUMEN

Epidemiological studies have robustly linked lower birth weight to later-life disease risks. These observations may reflect the adverse impact of intrauterine growth restriction on a child's health. However, causal evidence supporting such a mechanism in humans is largely lacking. Using Mendelian Randomization and 36,211 genotyped mother-child pairs from the FinnGen study, we assessed the relationship between intrauterine growth and five common health outcomes (coronary heart disease (CHD), hypertension, statin use, type 2 diabetes and cancer). We proxied intrauterine growth with polygenic scores for maternal effects on birth weight and took into account the transmission of genetic variants between a mother and a child in the analyses. We find limited evidence for contribution of normal variation in maternally influenced intrauterine growth on later-life disease. Instead, we find support for genetic pleiotropy in the fetal genome linking birth weight to CHD and hypertension. Our study illustrates the opportunities that data from genotyped parent-child pairs from a population-based biobank provides for addressing causality of maternal influences.


Asunto(s)
Diabetes Mellitus Tipo 2 , Hipertensión , Humanos , Peso al Nacer/genética , Diabetes Mellitus Tipo 2/genética , Genotipo , Relaciones Madre-Hijo
4.
Commun Biol ; 6(1): 71, 2023 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-36653477

RESUMEN

Varicose veins is the most common manifestation of chronic venous disease that displays female-biased incidence. To identify protein-inactivating variants that could guide identification of drug target genes for varicose veins and genetic evidence for the disease prevalence difference between the sexes, we conducted a genome-wide association study of varicose veins in Finns using the FinnGen dataset with 17,027 cases and 190,028 controls. We identified 50 associated genetic loci (P < 5.0 × 10-8) of which 29 were novel including one near ERG with female-specificity (rs2836405-G, OR[95% CI] = 1.09[1.05-1.13], P = 3.1 × 10-8). These also include two X-chromosomal (ARHGAP6 and SRPX) and two autosomal novel loci (TGFB2 and GJD3) with protein-coding lead variants enriched above 56-fold in Finns over non-Finnish non-Estonian Europeans. A low-frequency missense variant in GJD3 (p.Pro59Thr) is exclusively associated with a lower risk for varicose veins (OR = 0.62 [0.55-0.70], P = 1.0 × 10-14) in a phenome-wide scan of the FinnGen data. The absence of observed pleiotropy and its membership of the connexin gene family underlines GJD3 as a potential connexin-modulating therapeutic strategy for varicose veins. Our results provide insights into varicose veins etiopathology and highlight the power of isolated populations, including Finns, to discover genetic variants that inform therapeutic development.


Asunto(s)
Estudio de Asociación del Genoma Completo , Várices , Humanos , Femenino , Finlandia/epidemiología , Várices/epidemiología , Várices/genética , Enfermedad Crónica , Conexinas/genética
5.
Commun Med (Lond) ; 3(1): 4, 2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36653534

RESUMEN

BACKGROUND: Testosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes. METHODS: Leveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality. RESULTS: We show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes. CONCLUSIONS: Overall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences.


Hormones, such as testosterone, travel around the body communicating between the different parts. Testosterone is present at higher levels in men, but also present in women. Variable testosterone levels explain some differences in human traits and disease prevalence. Here, we study how adult testosterone levels relate to health and disease. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women's reproductive health, hormonal cancers, and hair growth typical in males. However, testosterone levels do not appear as a major cause of most traits studied, including psychiatric diseases and metabolic health. Normal variation in baseline testosterone levels thus seems to have a relatively minor impact on health and disease.

6.
PLoS One ; 15(12): e0243649, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33315912

RESUMEN

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). AIMS: We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. METHODS: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. RESULTS: Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during ß-blocker medication. CONCLUSIONS: Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.


Asunto(s)
Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Adolescente , Adulto , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Factores de Riesgo , Taquicardia Ventricular/epidemiología , Taquicardia Ventricular/terapia , Adulto Joven
7.
Mol Cell Endocrinol ; 479: 61-70, 2019 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-30196135

RESUMEN

Recent genome-wide association studies and mouse models have identified LIN28B as a gene affecting several pubertal timing-related traits and vertebrate growth. However, the exact biological mechanisms underlying the associations remain unknown. We have explored the mechanisms linking LIN28B with growth regulation by combining human gene expression data with functional models. Specifically, we show that 1) pubertal timing-associated genetic variation correlates with LIN28B expression in the pituitary and hypothalamus, 2) downregulating lin28b in zebrafish embryos associates with aberrant development of kiss2-neurons, and 3) increasing lin28b expression transiently by synthetic mRNA injections during embryogenesis results in sustained enhancement of zebrafish growth. Unexpectedly, the mRNA injections resulted in advanced sexual maturation of female fish, suggesting that lin28b may influence pubertal timing through multiple developmental mechanisms. Overall, these results provide novel insight into LIN28B function in vertebrate growth regulation, emphasizing the importance of the gene and related genetic pathways for embryonic and juvenile development.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Proteínas de Unión al ARN/genética , Proteínas de Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismo , Animales , Embrión no Mamífero/metabolismo , Desarrollo Embrionario/genética , Técnicas de Silenciamiento del Gen , Humanos , Hipotálamo/metabolismo , Larva/metabolismo , Hipófisis/metabolismo , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Factores de Tiempo , Regulación hacia Arriba/genética , Proteínas de Pez Cebra/metabolismo
8.
Sci Rep ; 9(1): 18060, 2019 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-31792362

RESUMEN

Genome-wide association studies (GWAS) have recurrently associated sequence variation nearby LIN28B with pubertal timing, growth and disease. However, the biology linking LIN28B with these traits is still poorly understood. With our study, we sought to elucidate the mechanisms behind the LIN28B associations, with a special focus on studying LIN28B function at the hypothalamic-pituitary (HP) axis that is ultimately responsible for pubertal onset. Using CRISPR-Cas9 technology, we first generated lin28b knockout (KO) zebrafish. Compared to controls, the lin28b KO fish showed both accelerated growth tempo, reduced adult size and increased expression of mitochondrial genes during larval development. Importantly, data from the knockout zebrafish models and adult humans imply that LIN28B expression has potential to affect gene expression in the HP axis. Specifically, our results suggest that LIN28B expression correlates positively with the expression of ESR1 in the hypothalamus and POMC in the pituitary. Moreover, we show how the pubertal timing advancing allele (T) for rs7759938 at the LIN28B locus associates with higher testosterone levels in the UK Biobank data. Overall, we provide novel evidence that LIN28B contributes to the regulation of sex hormone pathways, which might help explain why the gene associates with several distinct traits.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Sistema Hipotálamo-Hipofisario/metabolismo , Proopiomelanocortina/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Testosterona/sangre , Proteínas de Pez Cebra/metabolismo , Alelos , Animales , Animales Modificados Genéticamente , Sistemas CRISPR-Cas/genética , Biología Computacional , Conjuntos de Datos como Asunto , Receptor alfa de Estrógeno/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Técnicas de Inactivación de Genes , Humanos , Hipotálamo/metabolismo , Masculino , Modelos Animales , Hipófisis/metabolismo , Polimorfismo de Nucleótido Simple , RNA-Seq , Maduración Sexual/genética , Testosterona/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genética
9.
Int J Cardiol ; 250: 139-145, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29032884

RESUMEN

BACKGROUND: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. METHODS AND RESULTS: The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS). CONCLUSION: The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.


Asunto(s)
Variación Genética/genética , Taquicardia Ventricular/epidemiología , Taquicardia Ventricular/genética , Fibrilación Ventricular/epidemiología , Fibrilación Ventricular/genética , Adolescente , Adulto , Niño , Estudios de Cohortes , Femenino , Finlandia/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Mutación/genética , Análisis de Secuencia de ADN/métodos , Taquicardia Ventricular/diagnóstico , Fibrilación Ventricular/diagnóstico , Adulto Joven
10.
PLoS One ; 10(6): e0128524, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26030606

RESUMEN

Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP.


Asunto(s)
Centrómero , Cromosomas Humanos Par 2 , Crecimiento/genética , Pubertad/genética , Adolescente , Exoma , Femenino , Genoma Humano , Humanos , Masculino , Linaje , Análisis de Secuencia de ADN
11.
PLoS One ; 7(11): e48785, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23152804

RESUMEN

CONTEXT: Pubertal timing is under strong genetic control and its early onset associates with several adverse health outcomes in adulthood, including obesity, type 2 diabetes and cardiovascular disease. Recent data indicate strong association between pubertal timing and genetic variants near LIN28B, but it is currently unknown whether the gene contributes to the association between puberty and adult disease. OBJECTIVE: To elucidate the putative genetic link between early puberty and adult disease risk, we examined the association of two genetic variants near LIN28B with adult body size and metabolic profiles in randomly ascertained adult Finnish males and females. METHODS: Two single nucleotide polymorphisms (SNPs), rs7759938, the lead SNP previously associated with pubertal timing and height, and rs314279, previously also associated with menarcheal age but only partially correlated with rs7759938 (r(2) = 0.30), were genotyped in 26,636 study subjects participating in the Finnish population survey FINRISK. Marker associations with adult height, weight, body mass index (BMI), hip and waist circumference, blood glucose, serum insulin and lipid/lipoprotein levels were determined by linear regression analyses. RESULTS: Both rs7759938 and rs314279 associated with adult height in both sexes (p = 2×10(-6) and p = 0.001). Furthermore, rs314279 associated with increased weight in females (p = 0.001). Conditioned analyses including both SNPs in the regression model verified that rs314279 independently associates with adult female weight, BMI and hip circumference (p<0.005). Neither SNP associated with glucose, lipid, or lipoprotein levels. CONCLUSION: Genetic variants near the puberty-associated gene LIN28B associate with adult weight and body shape in females, suggesting that the gene may tag molecular pathways influencing adult adiposity-related traits.


Asunto(s)
Adiposidad/genética , Proteínas de Unión al ADN/genética , Estudios de Asociación Genética , Carácter Cuantitativo Heredable , Adulto , Anciano , Tamaño Corporal/genética , Femenino , Humanos , Masculino , Metaboloma/genética , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas de Unión al ARN , Población Blanca/genética
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA