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1.
Genet Sel Evol ; 51(1): 28, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221101

RESUMO

BACKGROUND: Single-step genomic best linear unbiased prediction (SSGBLUP) is a comprehensive method for genomic prediction. Point estimates of marker effects from SSGBLUP are often used for genome-wide association studies (GWAS) without a formal framework of hypothesis testing. Our objective was to implement p-values for single-marker GWAS studies within the single-step GWAS (SSGWAS) framework by deriving computational algorithms and procedures, and by applying these to a large beef cattle population. METHODS: P-values were obtained based on the prediction error (co)variances for single nucleotide polymorphisms (SNPs), which were obtained from the prediction error (co)variances of genomic predictions based on the inverse of the coefficient matrix and formulas to estimate SNP effects. RESULTS: Computation of p-values took a negligible time for a dataset with almost 2 million animals in the pedigree and 1424 genotyped sires, and no inflation of statistics was observed. The SNPs that passed the Bonferroni threshold of 10-5.9 were the same as those that explained the highest proportion of additive genetic variance, but even at the same significance levels and effects, some of them explained less genetic variance due to lower allele frequency. CONCLUSIONS: The use of a p-value for SSGWAS is a very general and efficient strategy to identify quantitative trait loci (QTL). It can be used for complex datasets such as those used in animal breeding, where only a proportion of the pedigreed animals are genotyped.


Assuntos
Peso ao Nascer/genética , Bovinos/genética , Marcadores Genéticos , Estudo de Associação Genômica Ampla/veterinária , Algoritmos , Animais , Conjuntos de Dados como Assunto , Feminino , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
2.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
3.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
4.
Eur J Epidemiol ; 34(6): 591-600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737679

RESUMO

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.


Assuntos
Peso ao Nascer , Neoplasias da Mama/epidemiologia , Peso ao Nascer/genética , Feminino , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de Risco
5.
Gene ; 694: 97-101, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30738962

RESUMO

BACKGROUND: Previous studies indicate that low birth weight and exposure to maternal stress during pregnancy may result in shortened telomeres in infants. Shorter telomere length has in turn been linked with accelerated ageing and with age-related diseases. This study aimed to investigate the association between pregnancy and birth factors and relative telomere length in offspring at 11 years of age. METHODS: Participants were aged 11 years enrolled in the Auckland Birthweight Collaborative Study at birth (n = 380). Half of the children were born small for gestational age (SGA = birthweight ≤ 10th percentile) and half were appropriate for gestational age (AGA = birthweight > 10th percentile). Maternal stress during pregnancy was assessed using the Perceived Stress Scale. Relative leukocyte telomere length (RTL) in leukocytes was measured at 11 years of age using quantitative real-time PCR. RESULTS: RTL was normally distributed (mean = 3.78, SD = 1.05). There were no significant associations between RTL at age 11 years and birthweight, sex, maternal smoking, maternal stress during pregnancy or maternal pre-pregnancy body mass index. CONCLUSION: At age 11 years, RTL did not differ between children by birthweight or pregnancy-related stressors. Further telomere-related studies in newborns, children and adolescents are merited to increase knowledge of potential telomere modulating factors.


Assuntos
Peso ao Nascer/genética , Estresse Psicológico/genética , Homeostase do Telômero/genética , Adulto , Peso ao Nascer/fisiologia , Índice de Massa Corporal , Criança , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Leucócitos , Masculino , Herança Materna/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Estresse Psicológico/metabolismo , Telômero/genética , Encurtamento do Telômero/genética
6.
J Anim Sci ; 97(2): 578-586, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30561683

RESUMO

Objectives were to estimate reciprocal effects of Romanov and Rambouillet breeds on survival, growth, and reproductive traits of F1 progeny and direct breed effects (Suffolk and Composite - ½ Columbia, » Hampshire, and » Suffolk) on survival and growth traits of the subsequent terminally sired lambs. Mature Rambouillet ewes (n = 243) were exposed to 20 Romanov rams over two seasons producing 621 lambs for evaluation of growth and survival traits with 274 F1 ewes being evaluated for reproduction traits through 4 yr of age. Similarly, mature Romanov ewes (n = 116) were exposed to 20 Rambouillet rams producing 601 lambs for evaluation of growth and survival traits with 176 F1 ewes being evaluated for reproduction traits through 4 yr of age. A total of 433 of those F1 ewes produced 3,431 lambs (1,552 litters) from 1,634 exposures to terminal sires over 4 yr. Terminal sires consisted of 38 Suffolk and 44 Composite rams. Reciprocal crossbred ewe lambs were produced from dramatically different uterine and neonatal environments, with litter size at birth from Romanov dams exceeding those from Rambouillet dams by 1.52 lambs (P < 0.001) and birth weight of lambs from Romanov dams averaged 3.41 kg compared with 4.26 kg from Rambouillet dams. Differences in BW were still evident at 140 d (P < 0.001) for dam-reared lambs. However, reciprocal ewe first breeding BW of both types were similar (P = 0.38). Minimal differences were observed in performance of reciprocal cross ewes through 4 yr for productivity, longevity, or progeny growth and survival. One exception was BW at 140 d where an interaction of dam breed with terminal sire breed reached significance for both dam-reared (P = 0.05) and nursery-reared (P = 0.02) lambs. This interaction was due to the lower weight of Composite-sired lambs out of reciprocal cross ewes born from Rambouillet dams. Composite rams increased number born (P < 0.01) and number weaned (P < 0.05) of the reciprocal cross ewes. Suffolk rams increased (P < 0.001) BW and growth rates from birth to 140 d of terminal progeny. Thus, there were little cumulative differences accrued over the 4 yr and no differences were detected for cumulative kilogram of lamb generated at 140 d per ewe exposed. The practical outcome of this evaluation was that performance levels of both types of Romanov crossbred ewes was similar allowing the industry to produce the desired crossbred ewes without needing large purebred ewe flocks of the less numerous Romanov breed.


Assuntos
Reprodução , Ovinos/fisiologia , Animais , Peso ao Nascer/genética , Cruzamento , Feminino , Tamanho da Ninhada de Vivíparos , Longevidade , Masculino , Parto , Fenótipo , Gravidez , Estações do Ano , Ovinos/genética , Ovinos/crescimento & desenvolvimento , Desmame
7.
Lipids Health Dis ; 17(1): 181, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30064420

RESUMO

BACKGROUND: Observational studies have illustrated that maternal central obesity is associated with birth size, including of birth weight, birth length and head circumference, but the causal nature of these associations remains unclear. Our study aimed to test the causal effect of maternal central obesity on birth size and puberty height growth using a Mendelian randomization (MR) analysis. METHODS: We performed two-sample MR using summary-level genome-wide public data. Thirty-five single nucleotide polymorphisms (SNPs), 25 SNPs and 41 SNPs were selected as instrumental variables for waist-to-hip ratio adjusted for BMI, waist circumference adjusted for BMI and hip circumference adjusted for BMI, respectively to test the causal effects of maternal central obesity on birth size and puberty height using an inverse-variance-weighted approach. RESULTS: In this MR analysis, we found no evidence of a causal association between waist circumference or waist-to-hip ratio and the outcomes. However, we observed that one standard deviation (SD) increase in hip circumference (HIP) was associated with a 0.392 SD increase in birth length (p = 1.1 × 10- 6) and a 0.168 SD increase in birth weight (p = 7.1 × 10- 5), respectively at the Bonferroni-adjusted level of significance. In addition, higher genetically predicted maternal HIP was strongly associated with the puberty heights (0.835 SD, p = 8.4 × 10- 10). However, HIP was not associated with head circumference (p = 0.172). CONCLUSIONS: A genetic predisposition to higher maternal HIP was causally associated with larger offspring birth size independent of maternal BMI. However, we found no evidence of a causal association between maternal waist circumference, waist-to-hip ratio and birth size.


Assuntos
Peso ao Nascer/genética , Estatura/genética , Obesidade Abdominal/genética , Circunferência da Cintura/genética , Índice de Massa Corporal , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Análise da Randomização Mendeliana , Obesidade Abdominal/patologia , Polimorfismo de Nucleotídeo Único , Gravidez , Puberdade/genética , Relação Cintura-Quadril
8.
J Anim Sci ; 96(7): 2545-2552, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29762720

RESUMO

This study evaluated reproductive, maternal performance, and longevity traits of 143 F1 cows sired by Brahman (Br), Boran (Bo), or Tuli (T) bulls from Angus or Hereford cows from 1994 to 2011. Cow traits were measured at 7 yr of age in 1999 and 2000 for 1992- and 1993-born cows, respectively. From 2004 to 2010, excluding 2008, incisor condition (solid, broken, smooth) scores were assigned to cows remaining in production; scores were evaluated with two models. Broken and solid mouths were each assigned a score of "1" and smooth assigned "0"; Br-sired (0.76) and Bo-sired cows (0.71) had higher scores (P < 0.05) than T-sired cows (0.54). When solid mouths were scored 1 and smooth and broken scored 0, Br-sired cows (0.34) were higher than T-sired (0.01) (P < 0.05), and Bo-sired (0.23) cows were not different from either (P > 0.05). Age level of the cow within birth year was important for all modeled calf traits (P < 0.05). Birth weights were not different among cow inheritance (P > 0.05). Cow type influenced (P < 0.05) 205-d adjusted weaning weight of calves; Br-sired dams (228.1 ± 2.37 kg) produced the greatest weaning weight, followed by Bo-sired (213.7 ± 3.10 kg), and T-sired (201.6 ± 2.69 kg) dams (P < 0.05). Adjusted means for calving rate for Bo-sired (0.92 ± 0.02) cows were higher (P < 0.05) than Br-sired (0.86 ± 0.02) and T-sired (0.86 ± 0.02) cows. Adjusted mean weaning rate was greater (P < 0.05) for Bo-sired cows (0.86 ± 0.02) than for cows sired by Br (0.77 ± 0.02) bulls, but weaning rate for T-sired cows (0.80 ± 0.02) were similar (P > 0.05). Cow weight was greater (P < 0.05) for Br-sired cows (590.5 ± 8.35 kg) than for Bo-sired (505.8 ± 10.46 kg) or T-sired cows (508.5 ± 9.37 kg). BCS at weaning for 7-yr-old cows was similar (P = 0.08) for Br-sired and Bo-sired cows and lower for T-sired cows (P = 0.0005, condition scores 6.0, 6.3, and 5.8, respectively). Boran-sired cows were older when they were removed from the herd, on average (12.7 ± 0.74 y, P = 0.03) than T-sired (10.6 ± 0.61 y); Br-sired cow persistence was intermediate and not different (11.05 ± 0.60 y, P > 0.06) from the others. Boran-sired cows had higher calving and weaning rates and better mouth scores than the other groups; consequently, they had greater longevity as well. Boran-sired and T-sired cows were moderate in size and weighed less than Br-sired cows throughout the study. Tuli-sired cows weaned the lightest calves and had the most tooth deterioration as they aged.


Assuntos
Peso ao Nascer/genética , Bovinos/fisiologia , Longevidade/genética , Parto/genética , Reprodução/genética , Animais , Cruzamento , Bovinos/genética , Feminino , Hereditariedade , Masculino , Herança Materna , Fenótipo , Gravidez , Desmame
9.
J Anim Sci ; 96(7): 2567-2578, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29762734

RESUMO

As a result of selecting for increased litter size, newborn piglets are being born lighter and have a lower chance of survival. Raising fewer pigs to market weight would have a negative impact on the industry and farmer profitability; thus, understanding the genetics of individual growth performance traits will determine whether these traits will play an important role in pig breeding schemes. This study aimed to estimate genetic parameters for individual birth weight (BW), weaning weight (WW), and probe weight (PW) in Canadian-purebred Yorkshire and Landrace pigs. PW is a live weight taken at the time of the ultrasound measurements, when pigs weigh about 100 kg. Data were collected from 2 large and related breeding herds from 2003 to 2015. Four linear animal models were used, which included the following: Model 1-direct additive genetic effect; Model 2-direct additive genetic and maternal genetic effect; Model 3-direct additive genetic and common litter effect; and Model 4-direct additive genetic, maternal genetic, and common litter effect. The model which included all 3 random effects (Model 4) was determined to be the best fit to the data. Low to moderate direct heritability estimates were observed as follows: 0.15 ± 0.03 for BW, 0.04 ± 0.01 for WW, and 0.33 ± 0.03 for PW for the Yorkshire breed; and 0.05 ± 0.01 for BW, 0.01 ± 0.01 for WW, and 0.27 ± 0.03 for PW in the Landrace breed. As expected, the direct heritability estimates increased with age as a result of decreased maternal influence on the trait. Bivariate animal models were also used to estimate genetic and environmental correlations between traits. Strong direct genetic correlations were observed between BW and WW in both breeds. Based on the estimates of genetic parameters, individual BW could be evaluated and considered in breeding programs aiming to increase BW and improve subsequent performance. Different selection emphasis could also be applied on direct and maternal additive genetic effects on BW to optimize the breeding programs and improve selection efficiency.


Assuntos
Peso ao Nascer/genética , Herança Materna , Suínos/genética , Animais , Peso Corporal/genética , Cruzamento , Canadá , Meio Ambiente , Feminino , Modelos Lineares , Tamanho da Ninhada de Vivíparos , Masculino , Parto , Fenótipo , Gravidez , Suínos/fisiologia , Desmame
10.
J Anim Sci ; 96(7): 2536-2544, 2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29741708

RESUMO

The objective of this study was to compare growth from birth to slaughter of different breed groups that were raised in Rio Grande do Sul, Brazil and estimate the consequent breed additive and heterosis effects. Caracu (C), Hereford (H), and Nelore (N) sires were mated with Angus (A) dams, and A sires were mated with H and N dams to produce a first generation of crossbred progeny that was contemporary with purebred A, H, and N calves. Heifers from this first generation (G1) were mated with Brangus (BN) and Braford (BO) sires to produce a second generation (G2) of progeny. Data were analyzed to estimate breed group means, individual and maternal breed additive effects, and heterosis effects on birth weight, weaning weight, preweaning average daily gain, yearling weight, postweaning average daily gain, fattening phase initial weight (around 19 mo), final weight (around 24 mo), average daily gain in the fattening phase, and age at slaughter. In general, crossbred calves outperformed purebred calves. Angus-N and CA crossbred cows weaned heavier calves. Individual taurine-indicine heterosis (Z) significantly increased weaning weight. The AN, NA, and CA steers were heaviest at yearling, whereas NA, CA, AN, and HA had the greatest final weights. However, AH steers were 1 mo older at slaughter than NA contemporaries. Taurine breed effects on postweaning traits and final weight were greater than for N. Maternal breed effects on birth weight and average daily gain in the fattening phase were greater for A and H than for N. In conclusion, heterosis effects were sufficiently large for use of N to be recommended as a component of such systems, despite their relatively low-breed additive effects compared with taurine breeds. Moreover, germplasm from the tropically adapted Bos taurus C may be particularly useful when increased milk production is desired. With the breed and heterosis effects derived in the present study, it is possible to predict the performance and infer which breed and breed crosses will perform better in crossbreeding systems designed for the subtropical conditions of southern Brazil and similar regions.


Assuntos
Peso ao Nascer/genética , Bovinos/crescimento & desenvolvimento , Vigor Híbrido , Reprodução , Animais , Brasil , Bovinos/genética , Bovinos/fisiologia , Cruzamentos Genéticos , Feminino , Hibridização Genética , Masculino , Parto , Fenótipo , Gravidez , Desmame , Ganho de Peso/genética
11.
BMC Med ; 16(1): 70, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29792231

RESUMO

BACKGROUND: Birthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations. METHODS: Genotype data were extracted from phase 3 of the 1000 Genomes Project for 2504 participants from 26 global populations grouped into five super-populations. GRB was calculated in offspring as the weighted sum of the number of birthweight-lowering genetic variants of 59 autosomal single-nucleotide polymorphisms associated with birthweight, and comparisons were made between Europeans and non-Europeans. RESULTS: GRB was significantly higher in Africans (mean difference 3.15; 95% confidence interval 2.64, 3.66), admixed Americans (3.02; 2.34, 3.70), East Asians (2.85; 2.29, 3.41), and South Asians (1.07; 0.49, 1.65) compared to Europeans. Birthweight-lowering genetic variants in Africans and East Asians were enriched for rare and frequency-fixed alleles (P < 0.001). African and Asian populations had the greatest deviation from the expectation of the common disease-common variant hyothesis. Compared to Europeans, the GRB of ancestral alleles was significantly higher and that of derived alleles was significantly lower in non-Europeans (P < 0.001). CONCLUSIONS: The burden of birthweight-lowering genetic variants is higher in Africans and East Asians. This finding is consistent with the high incidence of low birthweight in the two populations. The genetic variants we studied may not be causal and the extent to which they tag the causal variants in non-Europeans is unknown; however, our findings highlight that genetic variations contribute to population differences in birthweight.


Assuntos
Peso ao Nascer/genética , Variação Genética/genética , África , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino
12.
BMC Genomics ; 19(1): 290, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695247

RESUMO

BACKGROUND: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. METHODS: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.


Assuntos
Peso ao Nascer/genética , Metilação de DNA , Fumar , Adulto , Ilhas de CpG , Feminino , Sangue Fetal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Cadeias beta de Integrinas/genética , Masculino , Exposição Materna , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Gravidez , Proteínas Proto-Oncogênicas c-pim-1/genética
13.
Stat Appl Genet Mol Biol ; 17(2)2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29420308

RESUMO

Gene-environment (G×E) interaction plays a pivotal role in understanding the genetic basis of complex disease. When environmental factors are measured continuously, one can assess the genetic sensitivity over different environmental conditions on a disease trait. Motivated by the increasing awareness of gene set based association analysis over single variant based approaches, we proposed an additive varying-coefficient model to jointly model variants in a genetic system. The model allows us to examine how variants in a gene set are moderated by an environment factor to affect a disease phenotype. We approached the problem from a variable selection perspective. In particular, we select variants with varying, constant and zero coefficients, which correspond to cases of G×E interaction, no G×E interaction and no genetic effect, respectively. The procedure was implemented through a two-stage iterative estimation algorithm via the smoothly clipped absolute deviation penalty function. Under certain regularity conditions, we established the consistency property in variable selection as well as effect separation of the two stage iterative estimators, and showed the optimal convergence rates of the estimates for varying effects. In addition, we showed that the estimate of non-zero constant coefficients enjoy the oracle property. The utility of our procedure was demonstrated through simulation studies and real data analysis.


Assuntos
Peso ao Nascer/genética , Interação Gene-Ambiente , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Algoritmos , Índice de Massa Corporal , Idade Gestacional , Humanos , Recém-Nascido , Mães , Fenótipo
14.
J Anim Sci ; 96(4): 1246-1258, 2018 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-29471383

RESUMO

The objective of this study was to investigate the factors that influence calf health and survival in Charolais cattle. Data from 2,740 calves, originating from 16 French farms and observed from birth until 30 d of age, were analyzed using models that took account of direct genetic, maternal genetic, and common environmental effects. Both direct and maternal genetic parameters were estimated for birth weight (BW), calving ease (CE), neonatal vitality (NV), survival at 30 d (Surv), and umbilical infection and diarrhea at different ages (0 to 5 d: Umb1 and Diar1; 6 to 20 d: Umb2 and Diar2; and 21 to 30 d: Umb3 and Diar3). The heritability values for direct and maternal genetic effects were, 0.026 (SE = 0.027) and 0.096 (SE = 0.042) for Surv, 0.280 (SE = 0.063) and 0.063 (SE = 0.038) for BW, 0.129 (SE = 0.041) and 0 for CE, 0.073 (SE = 0.035) and 0 for NV, 0.071 (SE = 0.038) and 0.017 (SE = 0.026) for Umb1, 0 and 0.082 (SE = 0.029) for Umb2, 0 and 0.044 (SE = 0.030) for Diar1, 0.016 (SE = 0.022) and 0.012 (SE = 0.026) for Diar2, and 0.016 (SE = 0.028) and 0 for Diar3, respectively. Significant genetic variability in beef cattle was thus revealed for five calf health traits: NV, Surv, Diar1, Umb1, and Umb2. In addition, for three traits (Surv, Diar1, and Umb2), maternal genetic effects clearly contributed more to health performance than direct genetic effects. Estimates of genetic correlation between traits varied markedly (from 0 to 1 in absolute values) depending on the traits in question, the age for a given trait, and the type (direct or maternal) of the genetic effects considered. These results suggest that not all health traits in Charolais cattle can be improved simultaneously, and breeders will therefore have to prioritize certain traits of interest in their breeding objectives. Overall, our results demonstrate the potential utility of collecting and integrating data on calf diseases, NV and survival in future beef cattle breeding programs. To ensure appropriate biological and genetic evaluations of calf health performance, it is important to accurately describe the phenotypes for diarrhea and umbilical infections (in terms of age ranges) and account for maternal genetic and common environmental effects that explain calf health performance traits. Further investigation and improved data collection are now necessary to maximize the efficiency of breeding schemes designed to simultaneously improve production and health traits.


Assuntos
Doenças dos Bovinos/genética , Diarreia/veterinária , Resistência à Doença/genética , Nível de Saúde , Animais , Peso ao Nascer/genética , Cruzamento , Bovinos , Doenças dos Bovinos/mortalidade , Diarreia/genética , Diarreia/mortalidade , Feminino , Testes Genéticos , Masculino , Parto/genética , Fenótipo , Gravidez
15.
Diabetes ; 67(5): 1024-1029, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29463506

RESUMO

Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.


Assuntos
Peso ao Nascer/genética , Glicemia/metabolismo , Diabetes Gestacional/metabolismo , Macrossomia Fetal/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Peptídeo C/metabolismo , Região do Caribe , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Sangue Fetal/metabolismo , Desenvolvimento Fetal/genética , Macrossomia Fetal/metabolismo , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Recém-Nascido , Insulina/metabolismo , Masculino , Americanos Mexicanos/genética , Gravidez
16.
Medicine (Baltimore) ; 97(4): e9653, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29369181

RESUMO

Dexamethasone (DEX) could induce low birth weight of infant, and low birth weight has close associations with glucocorticoid levels, insulin resistance, hypertension, and metabolic syndrome in adulthood. This study was designed to reveal the action mechanisms of DEX on the birth weight of infant.Using quantitative real-time polymerase chain reaction (qRT-PCR), trophoblast cells of human placenta were identified and the optimum treatment time of DEX were determined. Trophoblast cells were treated by DEX (DEX group) or ethanol (control group) (each group had 3 samples), and then were performed with RNA-sequencing. Afterward, the differentially expressed genes (DEGs) were identified by R package, and their potential functions were successively enriched using DAVID database and Enrichr method. Followed by protein-protein interaction (PPI) network was constructed using Cytoscape software. Using Enrichr method and TargetScan software, the transcription factors (TFs) and micorRNAs (miRNAs) targeted the DEGs separately were predicted. Based on MsigDB database, gene set enrichment analysis (GSEA) was performed.There were 391 DEGs screened from the DEX group. Upregulated SRR and potassium voltage-gated channel subfamily J member 4 (KCNJ4) and downregulated GALNT1 separately were enriched in PDZ (an acronym of PSD-95, Dlg, and ZO-1) domain binding and Mucin type O-glycan biosynthesis. In the PPI network, CDK2 and CDK4 had higher degrees. TFs ATF2 and E2F4 and miRNA miR-16 were predicted for the DEGs. Moreover, qRT-PCR analysis confirmed that SRR and KCNJ4 were significantly upregulated.These genes might affect the roles of DEX in the birth weight of infant, and might be promising therapeutic targets for reducing the side effects of DEX.


Assuntos
Peso ao Nascer/genética , Dexametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Análise de Sequência de RNA , Trofoblastos/efeitos dos fármacos , Fator 2 Ativador da Transcrição/efeitos dos fármacos , Peso ao Nascer/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/efeitos dos fármacos , Fator de Transcrição E2F4/efeitos dos fármacos , Feminino , Humanos , Recém-Nascido , MicroRNAs/efeitos dos fármacos , N-Acetilgalactosaminiltransferases/efeitos dos fármacos , Placenta/citologia , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Gravidez , Reação em Cadeia da Polimerase em Tempo Real
17.
J Clin Endocrinol Metab ; 103(3): 917-925, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29342293

RESUMO

Context: Small for gestational age (SGA) can be the result of fetal growth restriction, which is associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the current study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more copy number variations (CNVs) and disturbed methylation and sequence variants may be present in genes associated with fetal growth. Design: A prospective cohort study of subjects with a low birth weight for gestational age. Setting: The study was conducted at an academic pediatric research institute. Patients: A total of 21 SGA newborns with a mean birth weight below the first centile and a control cohort of 24 appropriate-for-gestational-age newborns were studied. Interventions: Array comparative genomic hybridization, genome-wide methylation studies, and exome sequencing were performed. Main Outcome Measures: The numbers of CNVs, methylation disturbances, and sequence variants. Results: The genetic analyses demonstrated three CNVs, one systematically disturbed methylation pattern, and one sequence variant explaining SGA. Additional methylation disturbances and sequence variants were present in 20 patients. In 19 patients, multiple abnormalities were found. Conclusion: Our results confirm the influence of a large number of mechanisms explaining dysregulation of fetal growth. We concluded that CNVs, methylation disturbances, and sequence variants all contribute to prenatal growth failure. These genetic workups can be an effective diagnostic approach in SGA newborns.


Assuntos
Peso ao Nascer/genética , Retardo do Crescimento Fetal/genética , Recém-Nascido Pequeno para a Idade Gestacional , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Metilação de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos , Sequenciamento Completo do Exoma/métodos
18.
J Dairy Sci ; 101(3): 2158-2170, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29274962

RESUMO

A data set including 57,868 records for calf birth weight (CABW) and 9,462 records for weight at first insemination (IBW) were used for the estimation of direct and maternal genetic effects in Holstein Friesian dairy cattle. Furthermore, CABW and IBW were correlated with test-day production records and health traits in first-lactation cows, and with nonreturn rates in heifers. Health traits considered overall disease categories from the International Committee for Animal Recording diagnosis key, including the general disease status, diarrhea, respiratory diseases, mastitis, claw disorders, female fertility disorders, and metabolic disorders. For single-trait measurements of CABW and IBW, animal models with maternal genetic effects were applied. The direct heritability was 0.47 for CABW and 0.20 for IBW, and the direct genetic correlation between CABW and IBW was 0.31. A moderate maternal heritability (0.19) was identified for CABW, but the maternal genetic effect was close to zero for IBW. The correlation between direct and maternal genetic effects was antagonistic for CABW (-0.39) and for IBW (-0.24). In bivariate animal models, only weak genetic and phenotypic correlations were identified between CABW and IBW with either test-day production or health traits in early lactation. Apart from metabolic disorders, there was a general tendency for increasing disease susceptibilities with increasing CABW. The genetic correlation between IBW and nonreturn rates in heifers after 56 d and after 90 d was slightly positive (0.18), but close to zero when correlating nonreturn rates with CABW. For the longitudinal BW structure from birth to the age of 24 mo, random regression models with the time-dependent covariate "age in months" were applied. Evaluation criteria (Bayesian information criterion and residual variances) suggested Legendre polynomials of order 3 to modeling the longitudinal body weight (BW) structure. Direct heritabilities around birth and insemination dates were slightly larger than estimates for CABW and IBW from the single-trait models, but maternal heritabilities were exactly the same from both models. Genetic correlations between BW were close to 1 for neighboring age classes, but decreased with increasing time spans. The genetic correlation between BW at d 0 (birth date) and at 24 mo was even negative (-0.20). Random regression model estimates confirmed the antagonistic relationship between direct and maternal genetic effects, especially during calfhood. This study based on a large data set in dairy cattle confirmed genetic parameters and (co)variance components for BW as identified in beef cattle populations. However, BW records from an early stage of life were inappropriate early predictors for dairy cow health and productivity.


Assuntos
Peso ao Nascer/genética , Peso Corporal/genética , Bovinos/genética , Fertilidade/genética , Nível de Saúde , Animais , Teorema de Bayes , Cruzamento , Feminino , Lactação/genética , Modelos Genéticos , Parto , Fenótipo , Gravidez
19.
Infant Behav Dev ; 50: 64-77, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29149620

RESUMO

BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 genotype was obtained with buccal swabs and categorized according to the presence of the 7-repeat allele. Maternal depression was assessed with the Center for Epidemiologic Studies Depression Scale at the prenatal, 6-, 12-, and 24-month assessments. Maternal attention was measured at 6-months using a videotaped session of a 20-min non-feeding interaction. Attachment was assessed at 36-months using the Strange Situation Procedure. RESULTS: The presence of the DRD4 7-repeat allele was associated with less disorganized attachment, ß=-1.11, OR=0.33, p=0.0008. Maternal looking away frequency showed significant interactions with maternal depression at the prenatal assessment, ß=0.003, OR=1.003, p=0.023, and at 24 months, ß=0.004, OR=1.004, p=0.021, as at both time points, women suffering from depression and with frequent looking away behavior had an increased probability of disorganized attachment in their child, while those with less looking away behavior had a decreased probability of disorganized attachment in their child at 36 months. CONCLUSIONS: Our models support the contribution of biological and multiple environmental factors in the complex prediction of disorganized attachment at 36 months.


Assuntos
Atenção , Peso ao Nascer/genética , Depressão/genética , Interação Gene-Ambiente , Apego ao Objeto , Receptores de Dopamina D4/genética , Adolescente , Adulto , Atenção/fisiologia , Pré-Escolar , Estudos de Coortes , Depressão/psicologia , Feminino , Seguimentos , Genótipo , Humanos , Estudos Longitudinais , Masculino , Comportamento Materno/psicologia , Relações Mãe-Filho/psicologia , Valor Preditivo dos Testes , Gravidez , Estudos Prospectivos , Adulto Jovem
20.
Pediatr Obes ; 13(3): 133-140, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28008729

RESUMO

BACKGROUND: The genetic influence on child obesity has not been fully elucidated. OBJECTIVE: This study investigated the parental and child contributions of 83 adult body mass index (BMI)-associated single-nucleotide polymorphisms (SNPs) to obesity-related traits in children from birth to 5 years old. METHODS: A total of 1402 individuals were genotyped for 83 SNPs. An unweighted genetic risk score (GRS) was generated by the sum of BMI-increasing alleles. Repeated weight and length/height were measured at birth, 1, 2, 3 and 5 years of age, and age-specific and sex-specific weight and BMI Z-scores were computed. RESULTS: The GRS was significantly associated with birthweight Z-score (P = 0.03). It was also associated with weight/BMI Z-score gain between birth and 5 years old (P = 0.02 and 6.77 × 10-3 , respectively). In longitudinal analyses, the GRS was associated with weight and BMI Z-score from birth to 5 years (P = 5.91 × 10-3 and 5.08 × 10-3 , respectively). The maternal effects of rs3736485 in DMXL2 on weight and BMI variation from birth to 5 years were significantly greater compared with the paternal effects by Z test (P = 1.53 × 10-6 and 3.75 × 10-5 , respectively). CONCLUSIONS: SNPs contributing to adult BMI exert their effect at birth and in early childhood. Parent-of-origin effects may occur in a limited subset of obesity predisposing SNPs.


Assuntos
Peso Corporal/genética , Obesidade Pediátrica/genética , Ganho de Peso/genética , Adulto , Alelos , Peso ao Nascer/genética , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pais , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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