Preprocessing Tools for Data Preparation

This data preparation chapter is of paramount importance for implementing statistical machine learning methods for genomic selection. We present the basic linear mixed model that gives rise to BLUE and BLUP and explain how to decide when to use fixed or random effects that give rise to best linear unbiased estimates (BLUE or BLUEs) and best linear unbiased predictors (BLUP or BLUPs). The R codes for fitting linear mixed model for the data are given in small examples. We emphasize tools for computing BLUEs and BLUPs for many linear combinations of interest in genomic-enabled prediction and plant breeding. We present tools for cleaning, imputing, and detecting minor and major allele frequency computation, marker recodification, frequency of heterogeneous, frequency of NAs, and three methods for computing the genomic relationship matrix. In addition, scaling and data compression of inputs are important in statistical machine learning. For a more extensive description of linear mixed models, see Chap. 10.1007/978-3-030-89010-0_5.

Role of Single Nucleotide Variants in FSHR, GNRHR, ESR2 and LHCGR Genes in Adolescents with Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women, affecting up to 16.6% of reproductive-age women. PCOS symptoms in adolescents comprise oligomenorrhoea/amenorrhoea and biochemical and/or clinical hyperandrogenism. Long-term health risks of PCOS patients include infertility, metabolic syndrome, type 2 diabetes and cardiovascular disease. Genetic factors have been proven to play a role in development of the syndrome and its symptoms. Objective: To investigate single nucleotide variants (SNVs) in the GNRHR, ESR2, LHCGR and FSHR genes in adolescent patients with PCOS and their association with PCOS symptoms. Methods: We conducted a cross-sectional study comprising of 152 adolescents: 63 patients with PCOS, 22 patients at risk of developing PCOS and 67 healthy controls. Participants were recruited from out-patients attending a gynaecologist at the Children’s Clinical University Hospital, Riga, Latvia, between January 2017 and December 2020. Genomic DNA was extracted from whole blood, and SNVs in the GNRHR, ESR2, LHCGR and FSHR genes were genotyped. The distributions of SNV genotypes were compared among the three groups and genotype-phenotype associations within the PCOS group were evaluated. Results: No statistically significant differences were found in the distributions of genotypes for GNRHR (rs104893837), ESR2 (rs4986938), LHCGR (rs2293275) and FSHR (rs6166, rs6165, rs2349415) among PCOS patients, risk patients and healthy controls. Within the PCOS group, ESR2 rs4986938 minor allele homozygous patients had a significantly higher level of total testosterone than major allele homozygous patients and heterozygous patients. A significantly higher total testosterone level was also observed in PCOS patients carrying the LHCGR rs2293275 minor allele compared with major allele homozygous patients. Conclusions: The SNVs ESR2 rs4986938 and LHCGR rs2293275 play a role in the phenotypic characteristics of PCOS. To fully uncover their influence on the development of PCOS and its symptoms, further studies of larger cohorts and a follow up of this study sample through to adulthood are required. Furthermore, studies of adolescent PCOS patients conducted prior to the latest European Society of Human Reproduction and Embryology (ESHRE) criteria (2018) should be re-evaluated as the study groups might include risk patients according to these updated criteria, thereby potentially significantly impacting the published results.

Association of Genes of the NO Pathway with Altitude Disease and Hypoxic Pulmonary Hypertension

Chronic intermittent hypoxia leads to high-altitude pulmonary hypertension, which is associated with high asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. Therefore, we aimed to understand the relation of single nucleotide polymorphisms in this pathway to high-altitude pulmonary hypertension (HAPH). We genotyped 69 healthy male Chileans subjected to chronic intermittent hypoxia. Acclimatization to altitude was determined using the Lake Louise Score and the presence of acute mountain sickness. Echocardiography was performed after six months in 24 individuals to estimate pulmonary arterial pressure. The minor allele of dimethylarginine dimethylaminohydrolase (DDAH)1 rs233112 was associated with high-baseline plasma ADMA concentration, while individuals homozygous for the major allele of DDAH2 rs805304 had a significantly greater increase in ADMA during chronic intermittent hypoxia. The major allele of alanine glyoxylate aminotransferase-2 (AGXT2) rs37369 was associated with a greater reduction of plasma symmetric dimethylarginine (SDMA). Several genes were associated with high-altitude pulmonary hypertension, and the nitric oxide synthase (NOS)3 and DDAH2 genes were related to acute mountain sickness. In conclusion, DDAH1 determines baseline plasma ADMA, while DDAH2 modulates ADMA increase in hypoxia. AGXT2 may be up-regulated in hypoxia. Genomic variation in the dimethylarginine pathway affects the development of HAPH and altitude acclimatization.

Effects of functional variants of vitamin C transporter genes on apolipoprotein E E4-associated risk of cognitive decline: The Nakajima study

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Genetic variation in NDFIP1 modifies the metabolic patterns in immune cells of multiple sclerosis patients

One of the 233 polymorphisms associated with multiple sclerosis (MS) susceptibility lies within the NDFIP1 gene, and it was previously identified as eQTL in healthy controls. NDFIP1 shows interesting immune functions and is involved in the development of the central nervous system. We aimed at studying the NDFIP1 variant on activation and metabolism of immune cells. NDFIP1 mRNA and protein expression were assessed in PBMCs by qPCR and western blot in 87 MS patients and 84 healthy controls genotyped for rs4912622. Immune activation after PHA stimulation was evaluated by CD69 upregulation, and metabolic function of both basal and PHA-activated lymphocytes was studied by Seahorse Xfp-Analyzer. In minor-allele homozygous controls but not in patients, we found higher NDFIP1 expression, significantly reduced protein levels, and CD69 upregulation in B- and T-cells. PBMCs from minor-allele homozygous controls showed significantly higher basal mitochondrial respiration and ATP production compared to major-allele carriers, while minor-allele homozygous patients showed significantly lower metabolic activity than carriers of the major allele. In conclusion, we describe associations in minor-allele homozygous controls with lower levels of NDFIP1 protein, CD69 upregulation, and raised mitochondrial activity, which are not replicated in MS patients, suggesting a NDFIP1 differential effect in health and disease.

Impact of ABCG2 Gene Polymorphism on the Predisposition to Psoriasis

Psoriasis is a chronic inflammatory disease which is caused by the interaction between genetic and environmental factors. Evidence shows an association of psoriasis with co-morbidities including cardiovascular diseases, metabolic syndrome and hyperuricemia. Genome-wide association studies have revealed that the ABCG2 gene encoding ATP-binding cassette G2 protein was associated with inflammation and higher serum urate concentrations. In this study, we aimed to evaluate the role of ABCG2 gene polymorphisms on the susceptibility to psoriasis. The genotype distribution of two ABCG2 single nucleotide polymorphisms (SNPs), rs2231142 and rs2231137, was examined in 410 psoriasis patients and 1,089 gender-matched non-psoriasis controls. We found that heterozygotes (GT) for rs2231142 was associated with a decreased risk of psoriasis (p = 0.001; adjusted OR = 0.532; 95% CI, 0.370–0.765) after adjusting for age, as compared with homozygotes for the major allele (GG). Subjects who carried at least one polymorphic allele (homozygote or heterozygote for the minor allele) were less susceptible to psoriasis (p = 0.002; adjusted OR = 0.594; 95% CI, 0.249–0.823) and bearing higher serum urate levels (p = 0.026) than those homozygous for the major allele. Our results indicated that the ABCG2 gene polymorphism was associated with the risk of psoriasis.

Evaluation of Diversity among Soybean Genotypes via Yield Attributing Traits and SSR Molecular Markers

Introduction: As an important source of nutrients to humans and animals, soybean is considered to be a major crop. Objective: The present study has been executed to identify diverse soybean genotypes on account of different morpho-physiological and microsatellite molecular markers. Study Design: Data for Morpho-physiological traits were recorded from experiment conducted under field conditions in RBD design whereas molecular work was conducted in Laboratory. Place and Duration of the Study: The present study was conducted at College of Agriculture, Gwalior, Rajmata Vijayaraje Scindia Krishi Vishwa Vidyalaya, Gwalior, M.P., India during Kharif 2018-19. Methodology: The study was conducted to document different morphological and physiological traits related to the yield and its attributing traits in soybean. Total 32 microsatellite markers were also used in laboratory to analyze the variability among soybean genotypes. Results: Morpho-physiological analysis among 53 genotypes revealed the presence of considerable level of variability. Phylogenetic tree based on morpho-physiological traits grouped the genotypes into major and minor cluster. Major cluster had fifty genotypes while minor cluster had only three genotypes. Among polymorphic 32 microsatellite markers, the highest genetic diversity (0.66) was recorded in Satt520 whilst lowest (0.037) was in Satt557 with an average of 0.35. The highest PIC value was 0.59 prearranged by Satt520 and lowest 0.036 by Satt557. An average major allele frequency was 0.69 while, an average PIC value was 0.32. Microsatellite markers-based data also grouped the genotypes into one major and one minor cluster. Conclusion: Molecular analysis based on microsatellite markers confirms the presence of genetic variability among genotypes under the investigation. Data obtained in the present investigation may contribute towards improvement of soybean genotypes to develop high yielding varieties by considering diverse genotypes with good agronomical traits in hybridization programme.

Abstract P176: Genes That Increase Human Lifespan By Protecting Against Risk Of Death From Cardiometabolic Diseases

Further to our FOXO3 findings last year, we asked whether other longevity gene variants work by mitigating mortality risk from aging-related diseases. In a longitudinal study, 3,584 American men of Japanese ancestry from the Kuakini Honolulu Heart Program were followed from baseline (Exam 4, 1991-93) until Dec 31, 2019 (1% of men) or death (99%). At baseline, 2,512 subjects had either diabetes (n=1,010), hypertension (n=1,919) or coronary heart disease (CHD; n=738), and 1,072 lacked any cardiometabolic diseases (CMD). DNA samples for genotyping were obtained at baseline. Genotype frequencies of SNPs in MAP3K5 , PIK3R1 , GHR, CTGF , EGFR , FLT1 , SIRT5 and SIRT7 were compared between subjects with and without ageing-related diseases . In subjects with CMD, MAP3K5 rs2076260 longevity-associated genotypes CC and CC + TT were associated with longer lifespan (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12-1.35, p= 2.5x10 -5 ] in a major allele homozygote model, and 1.22 [95% CI: 1.11-1.33, p= 1.10x10 -5 ] in a heterozygote disadvantage model) compared with CT . For diabetes, hypertension and CHD, HR p -values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. For PIK3R1 , subjects with cardiovascular disease (CVD) having the longevity-associated genotypes TT / CC of SNP rs7709243 had survival curves similar to those of subjects without a CVD (HR 1.26 [95% CI, 1.14-1.39; p =0.0000043]). In contrast, survival curves of subjects with the CT genotype were significantly lower compared with survival curves of subjects without a CVD ( p =0.0000012 compared with TT / CC , and p =0.0000028 compared with CT ). For GHR SNP rs4130113 , in a heterozygote disadvantage model GG vs longevity-associated AG genotype was associated with reduced mortality risk from hypertension (HR 1.23 [95% CI, 0.94-1.41; p =0.0041]). Men without CVD showed no association of longevity-associated genotype with lifespan. For each gene, men without the disease outlived men with disease ( p < 10 -6 ), but genotype had no effect on lifespan. In conclusion, for MAP3K5 , PIK3R1 and GHR , but not other longevity genes, longevity genotype increases lifespan only in individuals who have CMD, CVD or hypertension, likely by protection against disease-related cellular stress.

Genotype–phenotype associations of polymorphisms within the gene locus of NOD-like receptor pyrin domain containing 3 in Swiss inflammatory bowel disease patients

Background Genetic variations within the regulatory region of the gene encoding NOD-like receptor pyrin domain containing 3 (NLRP3) have been associated with Crohn’s Disease (CD). NLRP3 is part of the NLRP3-inflammasome that mediates the maturation of IL-1β and IL-18. Carrying the major allele of the single nucleotide polymorphisms (SNPs) rs10733113, rs4353135 and rs55646866 is associated with an increased risk for CD. We here studied the impact of these polymorphisms on clinical characteristics in patients of the Swiss IBD Cohort Study (SIBDCS). Methods We included 981 Crohn’s disease (CD) patients and 690 ulcerative colitis (UC) patients of the SIBDCS. We analyzed whether three CD-associated NLRP3 polymorphisms have an impact on the clinical disease course in these patients. Results In CD patients presence of the major allele (G) of rs10733113 was associated with less surgeries and lower maximal CDAI and a similar trend was observed for rs55646866 and rs4353135. Presence of the major allele of all three SNPs was negatively correlated to maximal CDAI. In UC patients homozygous genotype for the major allele (CC) for rs55646866 was associated with a higher age at diagnosis and a higher MTWAI index. Homozygous genotype for the major allele of all three polymorphisms was associated with a higher number of ambulatory visits and longer hospital stays. Conclusions In CD patients presence of the major allele of all three polymorphisms was associated with markers of a less severe disease course, while in UC the homozygous genotype for all major alleles suggested a more severe disease activity.

The association between allergic rhinitis and Polymorphism of Toll like receptors 2 & 4 genes

Background: Allergic rhinitis is atopic disorder, 10% to 25% of the population worldwide are suffering from it, The prevalence is increasing during the last 10 years. Objectives: To study the relationship among polymorphism of single nucleotide in TLR2 and TLR4 genes and the risk of allergic rhinitis disease. Methodology: This study was done on 60 patients suffering from allergic rhinitis and 30 healthy subjects as a control group from April 2019 to March 2020. The patients were collected from Otorhinolaryngology Department of Benha University Hospital. Test of Skin prick (SPT) was done to assess atopic state. Blood samples were collected to detect TLR gene polymorphism by Polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Results: The genotypic frequencies of TLR2 Arg753Gln showed increased frequency of the homozygous (GG) genotype among the controls (80%) more than the allergic rhinitis patients (30%). The heterozygous (AG) genotype was increased among the allergic rhinitis patients (62.5%) more than in the healthy group (15%) with OR =9.4, 95% CI (2.4-37.7) and significant P-value. Also, the homozygous mutant (AA) genotype has more trend in the patients (7.5%) than in the control subjects (5%), with OR = 0. 6, 95% CI (0.1-6.7) and non-significant P-value. The genotypic frequencies Statistical data in TLR4 Asp299Gly revealed that the homozygous (AA) genotype has more frequency in the controls (70%) than the allergic rhinitis patients (20%). The heterozygous (AG) genotype was more prevalent among the allergic rhinitis patients (65%) than the controls (30%) with OR =4.3, 95% CI (1.4-13.8) and significant P-value. Conclusion: GG genotype of TLR2 and AA genotype of TLR4 are least affected by allergic rhinitis disease and the major allele in both gene is protective against the disease.