Genome-wide association and Mendelian randomization analyses of placental efficiency and piglet birth weight in Danish Large White pigs.

A novel Mendelian randomisation framework unravels one gene expression component, correlated with proliferation and genome stability-related features, associated with telomere length in lung adenocarcinoma tumours, which provides insights into how telomere length influences the genetic basis of lung cancer aetiology.

A novel Mendelian randomisation framework unravels one gene expression component, correlated with proliferation and genome stability-related features, associated with telomere length in lung adenocarcinoma tumours, which provides insights into how telomere length influences the genetic basis of lung cancer aetiology.

With the intensive increase in the fertility traits of sows, the problem of decreasing the weight of piglets at birth has arisen. In this connection, the search for genetic variants associated with the birth weight of piglets is of particular relevance and scientific significance. The aim of the work was to identify genetic variants associated with piglet weight at birth and test them to select optimal genetic markers for selection and breeding work to improve reproductive performance of pigs on the basis of full genomic genotyping data using the Fst method. The studies were conducted in 2020-2022 on Large White pigs (n=239) bred at CJSC Plemzavod-Yubileiny in the Tyumen Region. Genotyping was performed using GeneSeek® GGP Porcine HD Genomic Profiler v1 (Illumina Inc., USA). Genomic data were filtered according to the following parameters --geno 0.1, -mind 0.1, -maf 0.05, -hwe 1e-7, --indep-pairwise 50 5 0.8. To identify genomic regions associated with piglet birth weight, there was used Fst statistics comparing genetic variants in pigs between two groups with high and low indices. Those in which the Fst values exceeded the quantile level of 0.999 were considered significant variants. Student's test was used to evaluate the significance of the effects of variant genotypes on the birth weight and number of piglets at birth. The results showed that there was a moderate negative relationship (-0.351) between piglet birth weight and number of piglets at birth. 17 SNPs associated with birth weight of piglets were identified, 9 of which were located in the KIF13A, STK24, FDFT1, ADGRD1, STX2, TMEM132D, ENSSSCG00000054866, ENSSSCG00000058459 genes, as well as SNPs rs81450496, rs80887103 in intergenic regions have been identified as promising genetic markers for increase in birth weight of piglets. The results obtained can be used to create domestic breeding technologies that improve the efficiency of pig breeding.

Assessing causal relationship between non-alcoholic fatty liver disease and risk of atrial fibrillation

IntroductionLitter size in pigs has increased steadily since 1990. Because of unfavorable genetic correlations with piglet mortality, breeding goals should include survival traits next to litter size. Unbalanced breeding programs that neglect this requirement have produced increased mortality levels, attracting negative public attention. Balanced breeding does not have this disadvantage, but the general public is largely unaware of this.MethodsWe present long-term time trends as realized in commercial breeding. The data includes (i) phenotypes of litter size, piglet birth weight, and piglet mortality, as used in routine breeding value estimation; and (ii) the genomic Best Linear Unbiased Prediction (gBLUP) estimated breeding values thus obtained. Piglet mortality (2001–2022) and birth weight (2009–2022) phenotypes were related to litter size by recording year. Estimated breeding values (EBVs) for the mortality traits were regressed on those for litter size by birth year (2012–2022).ResultsAverage litter size is very weakly correlated to the mortality (R2 ≤ 0.06) and birth weight (0.07 ≤ R2 ≤ 0.26) traits, and those correlations are unfavorable (antagonistic) within each year. However, all traits analyzed here show favorable simultaneous phenotypic and genetic trends over time: the antagonisms are neutralized by balanced breeding. Above the annual mean litter size level, farrowing and lactation mortality rates increased with increasing litter size in every year (unfavorable), but the annual intercepts and the slopes decreased from 2001 to 2022 (favorable). Average litter birth weight decreased with litter size in every year (unfavorable), but the annual intercepts increased and the slopes decreased from 2009 to 2022 (favorable). The within-litter birth weight variation coefficient increased with litter size in every year (unfavorable), but the annual intercepts decreased from 2009 to 2022 (favorable). The proportion of low birth weights (i.e.,< 0.9 kg) for a given litter size is decreasing over time, and the critical birth weight level (below which lactation mortality increases strongly) is clearly population dependent and changes over time too.DiscussionThe increases in litter size and piglet survival rates due to balanced breeding policies lead to reduced total numbers of dead piglets (i.e., per country, per year) coinciding with a certain pig production volume (i.e., with a certain total number of weaned piglets).

Placental metal concentrations in relation to placental growth, efficiency and birth weight

Effect of dietary amino acid supplementation during gestation on placental efficiency and litter birth weight in gestating gilts

With the overall goal of increasing profitability by increasing litter size, two lines of pigs were divergently selected for four generations on an index of reproductive traits (n = 193 litters). The selection index (SI) included total born (TB), birth weight (BW) and placental weight (PW) and was designed to increase (H line) or decrease (L line) BW:PW (placental efficiency; PE). (Co)variance components were estimated for direct and maternal additive effects by using an animal model with MTDFREML procedures. Breeding values were estimated (EBV) for individual BW (n = 2,111), PW (n = 2,006), PE (n = 1,677), and SI (n = 1,677). Direct heritability estimates were 0.03, 0.25, 0.18, 0.11 and 0.08 for BW, PW, PE, SI, and TB, respectively. Genetic divergence was 20.7 g, 0.24, 0.11, and 0.07 pigs per generation for PW, PE, SI, and TB, respectively (P less 0.01), but not significant for BW. Thus, PW and PE are susceptible to change by genetic selection; however, the genetic trend for TB unexpectedly was positive in the L line The phase two objective was to evaluate correlated responses in conceptus development and placental function in these lines. Sows were remated within line to produce 50 generation-four litters for evaluation at d 30, 50, 70, 90, and 110 of gestation.Fetal weight did not differ between lines from d 30 to 90, but was lower in H than L at d 110 (P = 0.02). Crown-rump length did not differ between lines from d 30 to 70, but was longer in H than L at d 90 (P = 0.09) and shorter at d 110 (P = 0.04). PW did not differ between lines from d 30 to 90, but was lower in H than L at d 110 (P less than 0.01). PE did not differ between lines at any gestational age. These results suggest that in western breeds, a reduction in placental weight through selection is not accompanied by physiological changes to improve placental function and may result in decreased prenatal survival. The farrowing data were used in phase three to determine factors influencing survival at farrowing (FS) and weaning (WS). These traits were considered traits of the piglet and scored 1 for piglets alive at those time points or 0 if dead. Estimates of direct heritability were 0.16 and 0.18 and of maternal heritability were 0.14 and 0.10 for FS and WS, respectively. Logistic regressions indicated BW, PW, their interaction, and TB can be used as predictors FS and WS. In the presence of BW, PE does not improve the prediction of survival. These results suggest possible selection for increased FS and WS. A piglet's BW, PW, its litter average BW, and the individual's deviation from that average can be used to produce piglets with high survival probability.

This study investigated the influence of sow backfat thickness at 109 d of gestation on sow and piglet performance. Data from 846 farrowing multiparous Yorkshire sows with parity from 3 to 5 were collected from a pig breeding farm. Sows were divided into six groups based on backfat thickness (≤16, 17-18, 19-20, 21-22, 23-24, and ≥25 mm) at 109 d of gestation. The evaluation of reproductive performance included the litter size, litter weight at birth and at weaning of 21 d, weight of placenta at parturition, placental efficiency, and sow daily feed intake of lactation. Parameters related to plasma lipids and the placental-lipid concentration were measured. Data were analyzed to determine the relationships among backfat thickness, placental lipids, and piglet performance. No differences were observed in the number of piglets born, born alive, after cross-foster, and at weaning among groups (P > 0.05). The litter weight at birth and weaning, piglet birth weight, weaning weight, placental efficiency, and the number and percentage of piglets born with weight of <800 g showed a significantly quadratic effect of the backfat thickness (P < 0.05). During lactation, sow daily feed intake linearly decreased with increased backfat thickness at 109 d of gestation (P < 0.05). Although triglycerides and low-density lipoprotein cholesterol (LDL-C) showed no significant difference, cholesterol and high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) concentrations significantly increased (P < 0.05) in both maternal and umbilical cord blood with increased backfat thickness of sow. Placental-lipid concentrations also significantly increased (P < 0.05) with increased backfat thickness. Moreover, backfat thickness and placental-lipid concentration were positively correlated with the number of piglets weighing <800 g (P < 0.01) but negatively correlated with birth weight, litter birth weight, and piglet weaned weight (P < 0.01). In conclusion, backfat thickness of sow at end of gestation correlates with birth and weaning weight of piglets. Placental ectopic lipid accumulation-induced lipotoxicity is likely responsible for such correlation.

Piglet birth weight is associated with preweaning survival, and its related traits have been included in the breeding program. Thus, understanding its genetic basis is essential. This study identified four birth weight-associated genomic regions on chromosomes 2, 4, 5, and 7 through genome-wide association study analysis in 7286 pigs from three different pure breeds using the FarmCPU model. The genetic and phenotypic variance explained by the four candidate regions is 8.42% and 1.85%, respectively. Twenty-eight candidate genes were detected, of which APPL2, TGFBI, MACROH2A1, and SEC22B have been reported to affect body growth or development. In addition, 21 H3K4me3-enriched peaks overlapped with the birth weight-associated genomic regions were identified by integrating the genome-wide association study results with our previous ChIP-seq and RNA-seq data generated in the pig placenta, a fetal organ relevant to birth weight, and three of the regulatory regions influence TGFBI, MACROH2A1, and SEC22B expression. This study provides new insights into understanding the mechanisms for birth weight. Further investigating the variants in the regulatory regions would help identify the functional variants for birth weight in pigs.

The aim of this study was to determine the variability of birth weight and growth of piglets in hyper prolific sow line. Data collected from 25 litters from Pen Ar Lan Naima sow line were used to evaluate the variability of piglets' birth weight and its consequences on subsequent growth performances. All piglets were individually weighted five times from the birth until the end of nursery period. Pre-weaning mortality was the highest in piglets with birth weight less than 1,000 g. The difference in the final live weight at the end of nursery period between the lightest and heaviest piglets was more than 10 kg. Birth weight of piglets had a significant influence on pre-weaning mortality and subsequent growth performances. In large litters produced by highly prolific sows, the variability of birth weight of piglets together with an increased number of lighter piglets become a new challenge for pig producers.

BackgroundPiglet birth weight variability, a trait also known as the within-litter homogeneity of birth weight, reflects the sow’s prolificacy, because it is positively genetically correlated with preweaning mortality but negatively correlated with the mean growth of piglets during sucking. In addition, the maternal additive genetic variance and heritability has been found exist for this trait, thus, reduction in the variability of piglet birth weight to improve the sow prolificacy is possible by selective breeding.ResultsWe performed a genome wide association study (GWAS) in 82 sows with extreme standard deviation of birth weights within the first parity to identify significant SNPs, and finally 266 genome-wide significant SNPs (p < 0.01) were identified. These SNPs were mainly enriched on chromosome 7, 1, 13, 14, 15 and 18. We further scanned genes of the top 50 SNPs with the lowest p values and found some genes involved in plasma glucose homeostasis (GLP1R) and lipid metabolism as well as maternal-fetal lipid transport (AACS, APOB, OSBPL10 and LRP1B) which may contribute to the birth weight variability trait.ConclusionsBirth weight variability trait has a low heritability. It is not easy to get significant signal by GWAS using small sample size. Herein, we identified some candidate chromosome regions especially chromosome 7 and suggested five genes which may provide some information for the further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0309-6) contains supplementary material, which is available to authorized users.

Chinese Meishan pigs produce three to five more pigs per litter than less-prolific U.S. or European pig breeds as a result of a markedly decreased placental size and an increased pig weight: placental weight ratio (placental efficiency). We hypothesized that as a result of their intense selection for prolificacy, the Chinese had indirectly selected for a smaller, more efficient placenta in the Meishan breed. The goals of this study were to determine whether 1) significant variation in placental size and efficiency existed within our population of purebred Yorkshire pigs and 2) selection of pigs (boars and gilts) based on clear differences in placental size and efficiency would affect litter size. There was significant (approximately threefold) variation in placental efficiency in our herd of Yorkshire pigs, and marked (approximately twofold) variation existed within individual litters. We then selected pigs (boars and gilts) that had either a higher (A Group) or lower (B Group) than average placental efficiency. Although the birth weights of selected A Group pigs were similar to those of the B Group pigs, they had markedly smaller placentae. Males from each group (A or B) were bred to the females of the same group, and farrowing data were collected from parities 1 and 2. In both parities, A Group females farrowed more live pigs per litter than did B Group females (12.5 +/- .7 vs 9.6 +/- .5, P < .05). Although A Group pigs were on average approximately 20% lighter than B group pigs (1.2 +/- .1 vs 1.5 +/- .1 kg, P < .05), their placentae were approximately 40% lighter (250 +/- 10 vs 347 +/- 15 g, P < .01), resulting in a marked increase in placental efficiency. The results of this study suggest that selection on placental size and efficiency may provide a valuable tool for optimizing litter size in commercially important pig breeds.

BackgroundSystematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.Methods and findingsWe performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother–child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, ‘leave-one-out’, and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight −0.03 g [95% CI −2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15–9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (−20 g [95% CI −44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121–236 g, p = 1.43 × 10−9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.ConclusionsOur results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.

Clinical guidelines recommend the use of statins to reduce portal pressure and alleviate portal hypertension (PH). However, there is a lack of population-level studies on the use of non-statin Low-Density Lipoprotein Cholesterol (LDL-c) reduction agents for the treatment of PH. This study utilized a novel method, Mendelian Randomization (MR) analysis, to investigate the impact of commonly used LDL-c-lowering medications on PH. Instrumental variables (IVs) for eight lipid-lowering drug-related genes were extracted from three large-scale LDL-c databases of Genome-Wide Association Studies (GWAS), followed by MR analysis. The MR results indicated that, compared to normal individuals, lower expression of CETP and NPC1L1 in whole blood (result of meta-analysis: CETP [OR: 0.322, 95%CI:0.130–0.795, P = 1.396e-02], NPC1L1 [OR: 0.057, 95%CI: 0.022–0.146, P = 2.670e-09]) is associated with reduced portal pressure. The IVs of target genes were subjected to MR analysis with coronary atherosclerosis (CAD) as a positive control, confirming that the IVs can effectively substitute for the biological function of the target gene, thereby further enhancing the reliability of the results. Subsequently, Summary-based Mendelian Randomization (SMR) analysis was conducted by using expression quantitative trait loci (eQTL) data to validate the results of the MR analysis. The SMR results suggested that only NPC1L1 is associated with PH (OR: 0.648, 95%CI: 0.472–0.891, PSMR = 7.502e-3, PHEIDI = 0.747) from genetic correlation. Additionally, mediation analysis indicates that the therapeutic effect of NPC1L1 inhibitors on PH is partially mediated by tissue factor (mediating effect accounted for 18.52%, and the P value was 0.01). Phenome-Wide MR indicated that NPC1L1 inhibitors may be associated with 23 diseases or symptoms. In addition, NPC1L1 had genetic correlation between and alkaline phosphatase as well as total bilirubin, but no genetic correlation with alanine aminotransferase, aspartate aminotransferase, direct bilirubin, or gamma glutamyltransferase. In conclusion, this study systematically analyzed the genetic correlation between lipid-lowering drug targets and PH. From a genetic correlation perspective, we revealed that the potential therapeutic effect of NPC1L1 on PH may not be mediated through the reduction of LDL-c but rather through the modulation of tissue factors. Additionally, the potential side effects associated with NPC1L1 inhibition also were explored.