Efficacy of a Comprehensive Weight Reduction Intervention in Male Adolescents With Different FTO Genotypes.

BACKGROUND: The FTO gene polymorphisms may influence the effects of lifestyle interventions on obesity. The present study aimed to assess the influence of the rs9930506 FTO gene polymorphism on the success of a comprehensive weight loss intervention in male adolescents with overweight and obesity. METHODS: This study was carried out on 96 adolescent boys with overweight and obesity who were randomly assigned to the intervention (n = 53) and control (n = 43) groups. The blood samples of the participants were collected, and the FTO gene was genotyped for the rs9930506 polymorphism. A comprehensive lifestyle intervention including changes in diet and physical activity was performed for 8 weeks in the intervention group. RESULTS: Following the lifestyle intervention, BMI and fat mass decreased significantly in the intervention group compared with the control group (both p < 0.05), while no change was found in weight, height or body muscle percentage between the groups. The participants in the intervention group with the AA/AG genotype and not in carriers of the GG genotype had a significantly higher reduction in BMI (-1.21 vs. 1.87 kg/m2, F = 4.07, p < 0.05) compared with the control group. CONCLUSION: The intervention in individuals with the AA/AG genotype has been significantly effective in weight loss compared with the control group. The intervention had no association effect on anthropometric indices in adolescents with the GG genotype of the FTO rs9930506 polymorphism. TRIAL REGISTRATION: Name of the registry: National Nutrition and Food Technology Research Institute; Trial registration number: IRCT2016020925699N2; Date of registration: 24/04/2016; URL of trial registry record: https://www.irct.ir/trial/21447.

Genetic determinants of plasma protein levels in the Estonian population.

The proteome holds great potential as an intermediate layer between the genome and phenome. Previous protein quantitative trait locus studies have focused mainly on describing the effects of common genetic variations on the proteome. Here, we assessed the impact of the common and rare genetic variations as well as the copy number variants (CNVs) on 326 plasma proteins measured in up to 500 individuals. We identified 184 cis and 94 trans signals for 157 protein traits, which were further fine-mapped to credible sets for 101 cis and 87 trans signals for 151 proteins. Rare genetic variation contributed to the levels of 7 proteins, with 5 cis and 14 trans associations. CNVs were associated with the levels of 11 proteins (7 cis and 5 trans), examples including a 3q12.1 deletion acting as a hub for multiple trans associations; and a CNV overlapping NAIP, a sensor component of the NAIP-NLRC4 inflammasome which is affecting pro-inflammatory cytokine interleukin 18 levels. In summary, this work presents a comprehensive resource of genetic variation affecting the plasma protein levels and provides the interpretation of identified effects.

Whole-genome resequencing of Chinese indigenous sheep provides insight into the genetic basis underlying climate adaptation.

BACKGROUND: Chinese indigenous sheep are valuable resources with unique features and characteristics. They are distributed across regions with different climates in mainland China; however, few reports have analyzed the environmental adaptability of sheep based on their genome. We examined the variants and signatures of selection involved in adaptation to extreme humidity, altitude, and temperature conditions in 173 sheep genomes from 41 phenotypically and geographically representative Chinese indigenous sheep breeds to characterize the genetic basis underlying environmental adaptation in these populations. RESULTS: Based on the analysis of population structure, we inferred that Chinese indigenous sheep are divided into four groups: Kazakh (KAZ), Mongolian (MON), Tibetan (TIB), and Yunnan (YUN). We also detected a set of candidate genes that are relevant to adaptation to extreme environmental conditions, such as drought-prone regions (TBXT, TG, and HOXA1), high-altitude regions (DYSF, EPAS1, JAZF1, PDGFD, and NF1) and warm-temperature regions (TSHR, ABCD4, and TEX11). Among all these candidate genes, eight ABCD4, CNTN4, DOCK10, LOC105608545, LOC121816479, SEM3A, SVIL, and TSHR overlap between extreme environmental conditions. The TSHR gene shows a strong signature for positive selection in the warm-temperature group and harbors a single nucleotide polymorphism (SNP) missense mutation located between positions 90,600,001 and 90,650,001 on chromosome 7, which leads to a change in the protein structure of TSHR and influences its stability. CONCLUSIONS: Analysis of the signatures of selection uncovered genes that are likely related to environmental adaptation and a SNP missense mutation in the TSHR gene that affects the protein structure and stability. It also provides information on the evolution of the phylogeographic structure of Chinese indigenous sheep populations. These results provide important genetic resources for future breeding studies and new perspectives on how animals can adapt to climate change.

Interaction between HTR2A rs3125 and negative life events in suicide attempts among patients with major depressive disorder: a cross-sectional study.

BACKGROUND: Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA. METHODS: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions. RESULTS: Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515-3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009). CONCLUSION: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.

Association of the Single Nucleotide Polymorphisms in the Renin-Angiotensin-Aldosterone System with Hypertension in the Uzbek Population.

OBJECTIVE: This research aims to identify the association between the nine polymorphic variants (rs4961, rs699, rs4762, rs5186, rs1403543, rs1799998, rs5443, rs2070744, rs1799983) and the occurrence of hypertension and its clinical manifestations in the Uzbek population. METHODS: The study included 227 individuals, comprising 179 patients with hypertension and 48 controls. Clinical parameters such as age, weight, blood glucose, triglycerides, total cholesterol, low-density lipoprotein and high-density lipoprotein, blood urea nitrogen, creatinine, pulse wave velocity, left ventricular mass, and microalbuminuria levels were identified. We assessed the distribution of allele frequencies of these polymorphic variants in the Uzbek population to establish their association with cardiovascular diseases and their clinical manifestations. RESULTS: Genetic analysis of the polymorphic variants demonstrated a significant association of the AGT 521 C>T variant with arterial hypertension [P ≤ 0.01; Odds Ratio (OR) = 2.91]. The NOS3 -786 T>C variant correlated with left ventricular hypertrophy (P ≤ 0.05; OR = 0.35) and increased pulse wave velocity (P ≤ 0.01; OR = 0.21). The correlations of the AGTR2 1675 G>A variant with left ventricular hypertrophy (P ≤ 0.01; OR = 1.59) and increased pulse wave velocity (P ≤ 0.01; OR = 0.33) were identified. The AGT 704 T>C variant showed a significant association with increased pulse wave velocity (P ≤ 0.05; OR = 2.73). CONCLUSION: Four of the nine studied polymorphic variants were associated with clinical manifestations of hypertension in the Uzbek population. These variants can be used as genetic biomarkers to identify the risks of developing cardiovascular diseases and hypertension in the Uzbek population.

The Relationship Between CYP46A1 Polymorphism and Suicide Risk: A Preliminary Investigation.

Suicide is a global public health issue, with a particularly high incidence in individuals suffering from Major Depressive Disorder (MDD). The role of cholesterol in suicide risk remains controversial, prompting investigations into genetic markers that may be implicated. This study examines the association between CYP46A1 polymorphisms, specifically SNPs rs754203 and rs4900442, and suicide risk in a Mexican MDD patient cohort. Our study involved 188 unrelated suicide death victims, 126 MDD patients, and 144 non-suicidal controls. Genotypic and allelic frequencies were assessed using the Real Time-polymerase chain reaction method, and associations with suicide risk were evaluated using chi-square tests. The study revealed significant differences in allelic and genotypic frequencies in rs754203 SNP between suicide death and controls. The CYP46A1 rs754203 genotype G/G was significantly linked with suicide, and the G allele was associated with a higher risk of suicide (OR = 1.370, 95% CI = 1.002-1.873). However, we did not observe any significant differences in genotype distribution or allele frequencies of CYP46A1 rs4900442. Our study suggests that carriers of the CYP46A1 rs754203 G allele (A/G + G/G) may play a role in suicidal behavior, especially in males. Our findings support that the CYP46A1 gene may be involved in susceptibility to suicide, which has not been investigated previously. These results underscore the importance of further research in different populations to elucidate the genetic underpinnings of the role of CYP46A1 in suicide risk and to develop targeted interventions for at-risk populations.

The effects of ANRIL polymorphisms on colorectal cancer, tumor stage, and tumor grade among Iranian population.

BACKGROUND: Colorectal cancer (CRC) is a type of neoplasm, developing in the colon or rectum. The exact etiology of CRC is not well known, but the role of genetic, epigenetic, and environmental factors are established in its pathogenesis. Therefore, the aim of this research was to explore the effects of ANRIL polymorphisms on the CRC and its clinical findings. METHODS AND RESULTS: The peripheral blood specimens were collected from 142 CRC patients and 225 controls referred to Milad Hospital, Tehran, Iran. PCR- RFLP method was used to analyze ANRIL rs1333040, rs10757274 rs4977574, and rs1333048 polymorphisms. The ANRIL rs1333040 polymorphism was related to a higher risk of CRC in the co-dominant, dominant, and log-additive models. ANRIL rs10757274, rs4977574, and rs1333048 polymorphisms showed no effect on CRC susceptibility. The CGAA and TGGA haplotypes of ANRIL rs1333040/ rs10757274/ rs4977574/rs1333048 polymorphisms were associated with the higher and the lower risk of CRC respectively. The rs1333040 polymorphism was associated with higher TNM stages (III and IV). The frequency of ANRIL rs10757274 polymorphism was lower in CRC patients over 50 years of age only in the dominant model. In addition, the rs10757274 was associated with well differentiation in CRC patients. CONCLUSION: The ANRIL rs1333040 polymorphism was associated with a higher risk of CRC and higher TNM stages. ANRIL rs10757274 polymorphism was associated with the well-differentiated tumor in CRC.

Association between Gene Polymorphisms and SNP-SNP Interactions of the Matrix Metalloproteinase 2 Signaling Pathway and the Risk of Vascular Senescence.

Objective: This study aimed to explore the association of single nucleotide polymorphisms (SNP) in the matrix metalloproteinase 2 (MMP-2) signaling pathway and the risk of vascular senescence (VS). Methods: In this cross-sectional study, between May and November 2022, peripheral venous blood of 151 VS patients (case group) and 233 volunteers (control group) were collected. Fourteen SNPs were identified in five genes encoding the components of the MMP-2 signaling pathway, assessed through carotid-femoral pulse wave velocity (cfPWV), and analyzed using multivariate logistic regression. The multigene influence on the risk of VS was assessed using multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality regression (GMDR) modeling. Results: Within the multivariate logistic regression models, four SNPs were screened to have significant associations with VS: chemokine (C-C motif) ligand 2 (CCL2) rs4586, MMP2 rs14070, MMP2 rs7201, and MMP2 rs1053605. Carriers of the T/C genotype of MMP2 rs14070 had a 2.17-fold increased risk of developing VS compared with those of the C/C genotype, and those of the T/T genotype had a 19.375-fold increased risk. CCL2 rs4586 and MMP-2 rs14070 exhibited the most significant interactions. Conclusion: CCL2 rs4586, MMP-2 rs14070, MMP-2 rs7201, and MMP-2 rs1053605 polymorphisms were significantly associated with the risk of VS.

The association of FSCN1 (rs852479, rs1640233) and HOTAIR (rs920778) polymorphisms with the risk of breast cancer in Egyptian women.

BACKGROUND: Breast cancer (BC) is one of the most prevalent cancers that contribute to mortality among women worldwide. Despite contradictory findings, considerable evidence suggests that single nucleotide polymorphisms (SNPs) in the FSCN1 and HOTAIR genes may have a causative impact on the development of BC. This case-control study was conducted to evaluate the association of genotype frequency in FSCN1 rs852479, rs1640233, and HOTAIR rs920778 with susceptibility and prognosis of BC, as well as the impact of clinical stages and hormonal features. METHODS AND RESULTS: FSCN1 (rs852479, rs1640233) and HOTAIR (rs920778) were genotyped using TaqMan real-time PCR assay in 200 BC patients and 200 cancer-free controls, all representing Egyptian women. Genotypic analyses in association with clinicopathological factors and disease risk were assessed. As a result, a significant association with BC risk was observed for CC genotype frequency of FSCN1 rs852479 A > C (OR = 0.395, 95% CI 0.204-0.76, p-value = 0.005). However, no significant correlation was detected between the FSCN1 rs1640233 C > T and HOTAIR rs920778 C > T polymorphic variants and susceptibility to BC. Interestingly, CC genotype of FSCN1 rs1640233 was more likely to progress tumor size and lymph node invasion in BC cases (p-value = 0.04 and 0.02, respectively). Moreover, it was revealed that there was a non-significant correlation between the haplotype distributions of FSCN1 rs852479 and rs1640233 and the probability of BC. CONCLUSIONS: Based on the sample size and genetic characteristics of the subjects involved in the present study, our findings indicated that FSCN1 rs852479 may contribute to BC susceptibility in a sample of the Egyptian population.

Towards accurate indel calling for oncopanel sequencing through an international pipeline competition at precisionFDA.

Accurately calling indels with next-generation sequencing (NGS) data is critical for clinical application. The precisionFDA team collaborated with the U.S. Food and Drug Administration's (FDA's) National Center for Toxicological Research (NCTR) and successfully completed the NCTR Indel Calling from Oncopanel Sequencing Data Challenge, to evaluate the performance of indel calling pipelines. Top performers were selected based on precision, recall, and F1-score. The performance of many other pipelines was close to the top performers, which produced a top cluster of performers. The performance was significantly higher in high confidence regions and coding regions, and significantly lower in low complexity regions. Oncopanel capture and other issues may have occurred that affected the recall rate. Indels with higher variant allele frequency (VAF) may generally be called with higher confidence. Many of the indel calling pipelines had good performance. Some of them performed generally well across all three oncopanels, while others were better for a specific oncopanel. The performance of indel calling can further be improved by restricting the calls within high confidence intervals (HCIs) and coding regions, and by excluding low complexity regions (LCR) regions. Certain VAF cut-offs could be applied according to the applications.

Molecular mapping of the broad bean wilt virus 2 resistance locus bwvr in Capsicum annuum using BSR-seq.

KEY MESSAGE: Bulked segregant RNA seq of pools of pepper accessions that are susceptible or resistant to Broad bean wilt virus 2 identifies a gene that might confer resistance to this devastating pathogen. The single-stranded positive-sense RNA virus Broad bean wilt virus 2 (BBWV2) causes substantial damage to pepper (Capsicum annuum) cultivation. Here, we describe mapping the BBWV2 resistance locus bwvr using a F7:8 recombinant inbred line (RIL) population constructed by crossing the BBWV2-resistant pepper accession 'SNU-C' with the susceptible pepper accession 'ECW30R.' All F1 plants infected with the BBWV2 strain PAP1 were susceptible to the virus, and the RIL population showed a 1:1 ratio of resistance to susceptibility, indicating that this trait is controlled by a single recessive gene. To map bwvr, we performed bulked segregant RNA-seq (BSR-seq). We sequenced pools of resistant and susceptible lines from the RILs and aligned the reads to the high-quality 'Dempsey' reference genome to identify variants between the pools. This analysis identified 519,887 variants and selected the region from 245.9-250.8 Mb of the Dempsey reference genome as the quantitative trait locus region for bwvr. To finely map bwvr, we used newly designed high-resolution melting (HRM) and Kompetitive allele specific PCR (KASP) markers based on variants obtained from the BSR-seq reads and the PepperSNP16K array. Comparative analysis identified 11 SNU-C-specific SNPs within the bwvr locus. Using markers derived from these variants, we mapped the candidate bwvr locus to the region from 246.833-246.949 kb. SNU-C-specific variants clustered near DEM.v1.00035533 within the bwvr locus. DEM.v1.00035533 encodes the nitrate transporter NPF1.2 and contains a SNP within its 5' untranslated region. The bwvr locus, which contains four genes including DEM.v1.00035533, could represent a valuable resource for global pepper breeding programs.

Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study.

BACKGROUND: Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. METHODS: This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. RESULTS: The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. CONCLUSION: This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.

Characterizing the polygenic overlap and shared loci between rheumatoid arthritis and cardiovascular diseases.

BACKGROUND: Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. METHODS: Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. RESULTS: Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15-1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. CONCLUSIONS: This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.

Behavioural and physiological responses to stressors in sheep with temperament classified by genotype or phenotype.

The single nucleotide polymorphism (SNP) rs107856856, located in the tryptophan hydroxylase-2 gene, is associated with the behavioural phenotype for sheep temperament measured at weaning. Here, we tested the association between that SNP and physiological and behavioural responses to stressors in adult sheep. Two groups of adult sheep, one with genotype A/A (calm genotype) and the other with G/G (nervous genotype) in rs107856856, were selected from 160 sheep and were exposed, twice, to an open-field arena and an isolation box test (IBT). During each repeat, the behaviour and physiological responses (cortisol, prolactin, dehydroepiandrosterone [DHEA], brain derived neurotrophic factor [BDNF], characteristics of the response of body temperature, and oxidative stress) were measured. The behavioural and physiological responses of the sheep were compared between genotypes and also between groups classified on their phenotype as assessed by their initial isolation box score ("low responders" and "high responders"). The SNP rs107856856 had some effects on the behavioural phenotype (IBT score) but no effects on the physiological response to stress (cortisol, prolactin, DHEA, BDNF, oxidative stress or changes in body temperature) in the adult sheep, probably because the sheep were exposed, and therefore had adapted, to human contact during their life.

Haplotype function score improves biological interpretation and cross-ancestry polygenic prediction of human complex traits.

We propose a new framework for human genetic association studies: at each locus, a deep learning model (in this study, Sei) is used to calculate the functional genomic activity score for two haplotypes per individual. This score, defined as the Haplotype Function Score (HFS), replaces the original genotype in association studies. Applying the HFS framework to 14 complex traits in the UK Biobank, we identified 3619 independent HFS-trait associations with a significance of p < 5 × 10-8. Fine-mapping revealed 2699 causal associations, corresponding to a median increase of 63 causal findings per trait compared with single-nucleotide polymorphism (SNP)-based analysis. HFS-based enrichment analysis uncovered 727 pathway-trait associations and 153 tissue-trait associations with strong biological interpretability, including 'circadian pathway-chronotype' and 'arachidonic acid-intelligence'. Lastly, we applied least absolute shrinkage and selection operator (LASSO) regression to integrate HFS prediction score with SNP-based polygenic risk scores, which showed an improvement of 16.1-39.8% in cross-ancestry polygenic prediction. We concluded that HFS is a promising strategy for understanding the genetic basis of human complex traits.

Scattered throughout the human genome are variations in the genetic code that make individuals more or less likely to develop certain traits. To identify these variants, scientists carry out Genome-wide association studies (GWAS) which compare the DNA variants of large groups of people with and without the trait of interest. This method has been able to find the underlying genes for many human diseases, but it has limitations. For instance, some variations are linked together due to where they are positioned within DNA, which can result in GWAS falsely reporting associations between genetic variants and traits. This phenomenon, known as linkage equilibrium, can be avoided by analyzing functional genomics which looks at the multiple ways a gene's activity can be influenced by a variation. For instance, how the gene is copied and decoded in to proteins and RNA molecules, and the rate at which these products are generated. Researchers can now use an artificial intelligence technique called deep learning to generate functional genomic data from a particular DNA sequence. Here, Song et al. used one of these deep learning models to calculate the functional genomics of haplotypes, groups of genetic variants inherited from one parent. The approach was applied to DNA samples from over 350 thousand individuals included in the UK BioBank. An activity score, defined as the haplotype function score (or HFS for short), was calculated for at least two haplotypes per individual, and then compared to various complex traits like height or bone density. Song et al. found that the HFS framework was better at finding links between genes and specific traits than existing methods. It also provided more information on the biology that may be underpinning these outcomes. Although more work is needed to reduce the computer processing times required to calculate the HFS, Song et al. believe that their new method has the potential to improve the way researchers identify links between genes and human traits.

GbyE: an integrated tool for genome widely association study and genome selection based on genetic by environmental interaction.

BACKGROUND: The growth and development of organism were dependent on the effect of genetic, environment, and their interaction. In recent decades, lots of candidate additive genetic markers and genes had been detected by using genome-widely association study (GWAS). However, restricted to computing power and practical tool, the interactive effect of markers and genes were not revealed clearly. And utilization of these interactive markers is difficult in the breeding and prediction, such as genome selection (GS). RESULTS: Through the Power-FDR curve, the GbyE algorithm can detect more significant genetic loci at different levels of genetic correlation and heritability, especially at low heritability levels. The additive effect of GbyE exhibits high significance on certain chromosomes, while the interactive effect detects more significant sites on other chromosomes, which were not detected in the first two parts. In prediction accuracy testing, in most cases of heritability and genetic correlation, the majority of prediction accuracy of GbyE is significantly higher than that of the mean method, regardless of whether the rrBLUP model or BGLR model is used for statistics. The GbyE algorithm improves the prediction accuracy of the three Bayesian models BRR, BayesA, and BayesLASSO using information from genetic by environmental interaction (G × E) and increases the prediction accuracy by 9.4%, 9.1%, and 11%, respectively, relative to the Mean value method. The GbyE algorithm is significantly superior to the mean method in the absence of a single environment, regardless of the combination of heritability and genetic correlation, especially in the case of high genetic correlation and heritability. CONCLUSIONS: Therefore, this study constructed a new genotype design model program (GbyE) for GWAS and GS using Kronecker product. which was able to clearly estimate the additive and interactive effects separately. The results showed that GbyE can provide higher statistical power for the GWAS and more prediction accuracy of the GS models. In addition, GbyE gives varying degrees of improvement of prediction accuracy in three Bayesian models (BRR, BayesA, and BayesCpi). Whatever the phenotype were missed in the single environment or multiple environments, the GbyE also makes better prediction for inference population set. This study helps us understand the interactive relationship between genomic and environment in the complex traits. The GbyE source code is available at the GitHub website ( https://github.com/liu-xinrui/GbyE ).

Rare copy number variation in autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

[Research progress in genetics of noise-induced hearing loss].

Noise-induced hearing loss（NIHL） is an acquired sensorineural hearing loss induced by long-term noise exposure. The susceptibility of exposed people may vary even in the same noise environment. With the development of sequencing techniques, genes related to oxidative stress, immunoinflammatory, ion homeostasis, energy metabolism, DNA damage repair and other mechanisms in NIHL have been reported continuously. And some genes may interact with noise exposure indexes. In this article, population studies on NIHL-related gene polymorphisms and gene-environment interactions in the past 20 years are reviewed, aimed to providing evidence for the construction of NIHL-related risk prediction models and the formulation of individualized interventions.

Identification of superior and rare haplotypes to optimize branch number in soybean.

KEY MESSAGE: Using the integrated approach in the present study, we identified eleven significant SNPs, seven stable QTLs and 20 candidate genes associated with branch number in soybean. Branch number is a key yield-related quantitative trait that directly affects the number of pods and seeds per soybean plant. In this study, an integrated approach with a genome-wide association study (GWAS) and haplotype and candidate gene analyses was used to determine the detailed genetic basis of branch number across a diverse set of soybean accessions. The GWAS revealed a total of eleven SNPs significantly associated with branch number across three environments using the five GWAS models. Based on the consistency of the SNP detection in multiple GWAS models and environments, seven genomic regions within the physical distance of ± 202.4 kb were delineated as stable QTLs. Of these QTLs, six QTLs were novel, viz., qBN7, qBN13, qBN16, qBN18, qBN19 and qBN20, whereas the remaining one, viz., qBN12, has been previously reported. Moreover, 11 haplotype blocks, viz., Hap4, Hap7, Hap12, Hap13A, Hap13B, Hap16, Hap17, Hap18, Hap19A, Hap19B and Hap20, were identified on nine different chromosomes. Haplotype allele number across the identified haplotype blocks varies from two to five, and different branch number phenotype is regulated by these alleles ranging from the lowest to highest through intermediate branching. Furthermore, 20 genes were identified underlying the genomic region of ± 202.4 kb of the identified SNPs as putative candidates; and six of them showed significant differential expression patterns among the soybean cultivars possessing contrasting branch number, which might be the potential candidates regulating branch number in soybean. The findings of this study can assist the soybean breeding programs for developing cultivars with desirable branch numbers.

Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of maternal sensitivity on child attachment.

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the µ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that children carrying the G allele may be more likely to develop an ambivalent attachment pattern in response to less sensitive maternal care. The sample consisted of 191 mothers participating with their children (n = 223) in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, a community-based, birth cohort study of Canadian mothers and their children assessed longitudinally across the child's development. Maternal sensitivity was coded from at-home mother-child interactions videotaped when the child was 18 months of age. Child attachment was assessed at 36 months using the Strange Situation paradigm. As predicted, G allele carriers, but not AA homozygotes, showed increasing odds of being classified as ambivalently attached with decreasing levels of maternal sensitivity. Paralleling earlier non-human animal research, this work provides support for the theory that endogenous opioids contribute to the expression of attachment behaviors in humans.