Copies Of Haplotype Research Articles

Parenting behaviors, inhibitory control, and aggression: Moderation by serotonin receptor 2A haplotypes.

Despite the well-established relationship between parenting and child aggression, the mechanisms by which children incur this risk and whether genetic sources contribute to the heterogeneity in their vulnerability are not entirely clear. This study utilized a longitudinal sample of adolescents (n = 1,047, 50.2% females, Mage = 13.32 ± 0.48 years at Time 1) to examine the effects of positive and negative parenting on aggression, as mediated by inhibitory control and moderated by the serotonin receptor 2A (5-HTR2A) haplotype. Mediation analysis revealed that inhibitory control indirectly mediated the link between both positive and negative parenting and overt aggression but not relational aggression. Further, the indirect effect of negative parenting on overt aggression via inhibitory control was moderated by the 5-HTR2A haplotype. Compared to adolescents carrying zero copies of Thymine-Thymine haplotype, those with one copy of Thymine-Thymine haplotype had better inhibitory control when experiencing less negative parenting, which buffers the risk for overt aggression. However, the mediating role of inhibitory control did not hold in the positive parenting model. These findings elucidate the manner by which adolescents with different genetic predispositions develop aggressive behaviors in the context of family and suggest different etiology of overt and relational aggression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A variant in the 5′UTR of ERBB4 is associated with lifespan in Golden Retrievers

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer’s disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5′UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

Genetic glucocorticoid receptor variants differ between ethnic groups but do not explain variation in age of diabetes onset, metabolic and inflammation parameters in patients with type 2 diabetes.

The effect of excess glucocorticoid receptor (GR) stimulation through glucocorticoid medication or cortisol on glucose metabolism is well established. There are genetic GR variants that result in increased or decreased GR stimulation. We aimed to determine the prevalence of genetic GR variants in different ethnic groups in a cohort of patients with type 2 diabetes, and we aimed to determine their association with age of diabetes onset and metabolic and inflammation parameters. A cross-sectional analysis was performed in a multiethnic cohort (n = 602) of patients with established type 2 diabetes. Polymorphisms in the GR gene that have previously been associated with altered glucocorticoid sensitivity (TthIIII, ER22/23EK N363S, BclI and 9β) were determined and combined into 6 haplotypes. Associations with age of diabetes onset, HbA1c, hs-CRP and lipid values were evaluated in multivariate regression models. The prevalence of the SNPs of N363S and BclI was higher in Dutch than in non-Dutch patients. We observed a lower prevalence of the SNP 9β in Dutch, South(East) Asian and Black African patients versus Turkish and Moroccan patients. We did not detect an association between SNPs and diabetes age of onset or metabolic parameters. We only found a trend for lower age of onset and higher HbA1c in patients with 1 or 2 copies of haplotype 3 (TthIIII + 9β). The prevalence of genetic GR variants differs between patients of different ethnic origins. We did not find a clear association between genetic GR variants and age of diabetes onset or metabolic and inflammation parameters. This indicates that the clinical relevance of GR variants in patients with established type 2 diabetes is limited.

A DNA test for high incidence of soft scald and soggy breakdown postharvest disorders in Malus domestica Borkh

The ‘Honeycrisp’ apple, an economically important cultivar and breeding parent, is prone to soft scald and soggy breakdown postharvest physiological disorders. Phenotypic evaluation of soft scald is time consuming and costly, making it an excellent target for DNA-informed breeding. The objective of this study was to develop a DNA test for a soft scald and soggy breakdown quantitative trait locus (QTL) on linkage group two (LG2) that was characterized in a previous study. ‘Honeycrisp’ is homozygous for the undesirable high disorder incidence haplotype (HDI) at this QTL. In this study, sixteen single nucleotide polymorphism markers were evaluated for their associations with the HDI haplotype in a set of 132 unique cultivars and important breeding parents. A DNA test was successfully developed utilizing KASP™ (Kompetitive Allele Specific PCR) chemistry to identify the number of HDI haplotypes in individuals. This test had a 100% accuracy for detecting homozygous unfavorable HDI individuals and has an expected 88% accuracy over all three haplotype copy groups across the evaluated germplasm. This DNA test is a promising tool for minimizing the chances of selecting individuals that exhibit high incidence of soft scald postharvest disorder in ‘Honeycrisp’-related germplasm.

Association of TLR2 haplotypes encoding Q650 with reduced susceptibility to ovine Johne\u2019s disease in Turkish sheep

Ovine Johne’s disease (OJD) is caused by Mycobacterium avium subsp. paratuberculosis (MAP) and carries a potential zoonotic risk for humans. Selective breeding strategies for reduced OJD susceptibility would be welcome tools in disease eradication efforts, if available. The Toll-like receptor 2 gene (TLR2) plays an important signaling role in immune response to MAP, and missense variants are associated with mycobacterial infections in mammals. Our aim was to identify and evaluate ovine TLR2 missense variants for association with OJD in Turkish sheep. Eleven TLR2 missense variants and 17 haplotype configurations were identified in genomic sequences of 221 sheep from 61 globally-distributed breeds. The five most frequent haplotypes were tested for OJD association in 102 matched pairs of infected and uninfected ewes identified in 2257 Turkish sheep. Ewes with one or two copies of TLR2 haplotypes encoding glutamine (Q) at position 650 (Q650) in the Tir domain were 6.6-fold more likely to be uninfected compared to ewes with arginine (R650) at that position (CI95 = 2.6 to 16.9, p-value = 3.7 × 10–6). The protective TLR2 Q650 allele was present in at least 25% of breeds tested and thus may facilitate selective breeding for sheep with reduced susceptibility to OJD.

Genome-wide association study for beef fatty acid profile using haplotypes in Nellore cattle

The objective of this study was to identify genomic regions associated with beef fatty acid (FA) profile in Nellore cattle finished in feedlot, using haplotype based analyzes. Also, the metabolic pathway enrichment analysis was performed to seek for genes with known functions, close to the haplotype blocks, associated with the evaluated traits, providing subsidies for a better understanding of how the genes affect this trait. A total of 963 Nellore bulls with phenotype for FA, were genotyped using the Illumina BovineHD BeadChip. Samples from the Longissimus thoracis muscle were taken for FAs profile measurement by gas chromatography using a SP-2560 capillary column. Haplotype blocks were defined based on the linkage disequilibrium (LD), where pairs of SNPs are in strong LD if the confidence interval is equal to or greater than 95% with D’ equal to 0.98 and the lower limit is above 0.70. The model used to estimate the haplotypes effects for the sum of beef fatty acid groups included the fixed effects of contemporary group, animal age at slaughter (as linear covariable), haplotypes (as linear regression over the number of haplotype copies: 0, 1 e 2), and the additive genetic effect as random (polygenic effect). Genome-wide association analyzes were performed for each haplotype block (single marker association) by a Restricted Maximum Likelihood model (REML) using ASREML v. 4.3 software. A total of 15, 15, 4, 3, 6, 5, and 10 haplotypes were significantly associated (FDR< 0.10) with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), total amount of saturated fatty acids (SFA), PUFA:SFA ratio, omega 3 (n3), omega 6 (n6), and n6:n3 ratio, respectively. The statistically significant haplotypes harbored 38 genes, among which we highlighted those involved in lipid biosynthesis and metabolism, low-density lipoprotein oxidation, transport of fatty acids and cholesterol, adipocyte functions, biosynthesis of glycoprotein hormones, regulation of serum triglyceride and high-density lipoprotein-cholesterol levels, and adipogenesis. In addition, several novel regions were identified, including a putative quantitative trait locus for lipid metabolism and energy homeostasis. The enrichment analysis by DAVID tool revealed 14 significant (P< 0.05) terms related to fatty acids such as cellular response to retinoic acid, glycerol transport, regulation of Notch signaling pathway, and Ras signaling pathway. These results would contribute to the improvement of nutritional and health value of beef lipids in indicine cattle by including information from causal mutations in genetic evaluation through weighted their effects differently in genomic predictions.

Investigation of eNOS gene polymorphism exposes a genetic association between endothelial dysfunction and osteoporosis in postmenopausal women.

To investigate the association of genetic polymorphisms of endothelial nitric oxide synthase (eNOS) gene with endothelial dysfunction associated osteoporosis in postmenopausal women of Punjab, India. The study involved 456 postmenopausal women having endothelial dysfunction categorized according to women with (n = 236) and without osteoporosis (n = 220). Bone mineral density (BMD) and reactive hyperemia index (RHI) were evaluated together with six single-nucleotide polymorphisms (SNPs) within the eNOS gene (rs2070744, rs1799983, rs1800780, rs3918181, rs891512, and rs1808593). A moderate association between RHI and BMD at femoral neck (r = 0.213, P = 0.002) and lumbar spine (r = 0.267, P < 0.001) was observed. Minor alleles C and T of SNPs rs2070744 and rs1799983 were associated with chances of osteoporosis in both co-dominant (odds ratio [OR] 2.13, P = 0.017; OR 2.77, P = 0.009) and dominant (OR 2.10, P = 0.011; OR 2.45, P = 0.007) modes, whereas minor allele A of SNP rs891512 showed marginal probability in dominant model (OR 1.68, P = 0.047). A susceptibility haplotype (CTAAAT) was observed within the eNOS gene which conferred 2.32 times higher chances of osteoporosis (OR 2.32, 95% confidence interval 1.18-4.54, P = 0.021) after adjusting for the effect of confounders. Genetic model analysis revealed that each copy of susceptibility haplotype increased the possibility of osteoporosis by a factor of 2.11 ± 0.63 (P < 0.001). RHI was significantly associated with susceptibility haplotype CTAAAT in a dose-dependent manner, whereby the severity of endothelial dysfunction increased significantly in women having two copies over women having one copy or no copy (β = 2.13, P < 0.001) of susceptibility haplotype. A susceptibility haplotype CTAAAT within the eNOS gene is associated with double the possibility of endothelial dysfunction affiliated osteoporosis in postmenopausal women of Punjab, India.

Oligonucleotide hybridization with magnetic separation assay for multiple SNP phasing

Since humans have two copies of each gene, multiple mutations in different loci may or may not be found on the same strand of DNA (i.e., inherited from one parent). When a person is heterozygous at more than one position, the placement of these mutations, also called the haplotype phase, (i.e., cis for the same strand and trans for different strands) can result in the expression of different amount and type of proteins. In this work, we described an enzyme-free method to phase two single nucleotide polymorphisms (SNPs) using two fluorophore/quencher-labelled probes, where one of which was biotinylated. The fluorescence signal was obtained twice: first, after the addition of the labelled probes and second, after the addition of the magnetic beads. The first signal was shown to be proportional to the total number of SNP A and SNP B present in the target analyte, while the second signal showed a marked decrease of the fluorescence signal from the non-biotinylated probe when the SNPs were in trans, showing that the probe immobilized on the magnetic bead selectively captures targets with SNPs in a cis configuration. We then mimic the nature of the human genome which consists of two haplotype copies of each gene, and showed that 250 nM of the 10 possible pairs of haplotypes could be differentiated using a combination of fluorescence microscopy and fluorescence detection.

Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis

BackgroundInterleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1β) and tumor necrosis factor–alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent. MethodsSix single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (−174G/C), rs1800796 (−572G/C), rs1800797 (−597G/A), rs2069827 (−1363G/T), rs12700386 (−2954G/C) and rs10499563 (−6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1β and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA). ResultsAllele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P < 0.01) in all the three genetic models; co-dominant (OR 4.08 & 4.12, P < 0.001), recessive (OR 3.00 & 2.51, P < 0.001) and dominant (OR 2.56 & 3.09, P < 0.05). Major allele G of rs1800796 and rs1800797 was observed to enhance OA risk in recessive mode (OR 1.75, P < 0.001 & 1.62, P = 0.01 respectively). Disease risk analysis after adjusting the effect of confounders exposed a susceptibility haplotype GGGGCT, which increased the OA risk by 2.27 times (OR 2.27, 95%CI: 1.26–4.10, P = 0.009) and a protective haplotype CGAGGC which significantly reduced the OA risk (OR 0.47, 95%CI 0.27–0.92, P = 0.031). Both of these haplotypes manifested in the recessive mode of inheritance. Subjects who had one copy of the susceptibility haplotype had lower values of IL-6 (3.6 pg/ml) and IL-1β levels (3.2 pg/ml) than those who had 2 copies of it (4.4 pg/ml & 4.2 pg/ml respectively). IL-6 and IL-1β levels were observed to be negatively associated with protective haplotype CGAGGC (P < 0.05). Carriers of 1 copy of this haplotype showed decreased IL-1β levels than those who had none (1.00 pg/ml vs. 1.3 pg/ml respectively) which further decreased to 0.9 pg/ml in those subjects who carried two copies of protective haplotype. ConclusionThe present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1β for the risk of osteoarthritis in the population of Punjab, India.

Association of two single nucleotide polymorphisms in the calpastatin gene with tenderness under varying lengths of meat ageing in two native Spanish cattle breeds

The objective of this study was to validate the effect of the SNPs rs210072660 and rs109221039 of the calpastatin (CAST) gene on meat toughness in Longissimus thoracis muscle aged for 1 d (±0; short-term ageing), 8 d (±1; medium-term ageing) and 15 d (±2; long-term ageing). The samples were obtained in experiments with different management strategies in Parda de Montaña (grazing and concentrate-fed bulls, grazing steers, and steers finished on a total mixed ration) and Pirenaica (concentrate-fed bulls, steers and heifers, and steers on a total mixed ration) cattle. In the Parda de Montaña breed, the Warner-Bratzler Shear Force (WBSF) was similar among management strategies under short-term aging, but it was lower for concentrate-fed bulls than for grazing bulls under medium-term and long-term aging (P < 0.05), presenting both groups of forage-fed steers intermediate values. Similarly, there were no differences in the short-term ageing, but there were differences observed thereafter in the Pirenaica breed. Regarding the effect of SNPs of CAST in the Parda de Montaña breed, WBSF was only affected by the interaction between the SNP rs210072660 and ageing (P < 0.05). Shear force did not differ among genotypes (P > 0.05) under short-term ageing, but the GG genotype had 14–16% greater WBSF than the GA and AA genotypes under medium-term ageing (P < 0.001), and a trend was found under long-term ageing (P = 0.07). In Pirenaica, WBSF was only affected by SNP rs109221039 (P < 0.001). The GG genotype showed higher WBSF than the GA and AA genotypes under medium-term and long-term ageing (P < 0.01). Haplotype analyses confirmed the association results. In the Parda de Montaña breed, animals carrying no copies of haplotype AA had a greater WBSF under medium-term ageing than animals with 1 or 2 copies of this haplotype (P < 0.05). In the AG haplotype, animals with 0 copies of this haplotype had greater toughness than animals with 1 copy (P < 0.05). In Pirenaica breed, animals with 2 copies of the GG haplotype had greater toughness than animals with 1 or 2 copies in both ageing periods (P < 0.001). These findings suggest that SNPs rs210072660 and rs109221039 could be useful markers for effective marker-assisted selection to increase meat tenderness in the Parda de Montaña and Pirenaica breeds, respectively.

Human leukocyte antigen-G 3′ untranslated region polymorphism +3142G/C (rs1063320) and haplotypes are associated with manifestations of the American Tegumentary Leishmaniasis in a Northeastern Brazilian population

While the role of cytokine genes has been well documented in the context of Leishmania (Viannia) braziliensis infection, no studies have addressed the influence of human leukocyte antigen-G (HLA-G) in susceptibility/resistance to American Tegumentary Leishmaniasis (ATL). Here, we evaluated the influences of HLA-G, IL-10, TNF-A and IFN-G in the susceptibility and clinical manifestations of ATL.DNA of 114 ATL patients and 346 healthy individuals were sequenced for well-documented polymorphisms in HLA-G 3′ untranslated region (UTR), in IL-10 and TNF-A promoters and in IFN-G intron 1. Soluble HLA-G (sHLA-G) and cytokine levels were evaluated by ELISA and flow cytometry, respectively. Analyses were performed using GraphPad and R-package software.Individuals bearing HLA-G +3142G/G showed an association with increased risk for ATL, whereas those carrying the HLA-G +3142C/G and one copy of UTR6 haplotype, showed an association with decreased risk for ATL. sHLA-G was overexpressed in “susceptible” patients compared to the “resistant’’ one, and also in patients bearing +3142G/G genotype.From these results, HLA-G +3142G/G may be considered as genotype of susceptibility and UTR6 as marker of protection to ATL. Our findings showed a participation of HLA-G in the pathogenesis of the ATL.

T152. NRN1 GENE AND FUNCTIONAL MRI: ASSOCIATION ANALYSIS IN SCHIZOPHRENIA PATIENTS AND HEALTHY SUBJECTS

BackgroundAlterations of synaptic plasticity are currently accepted to play a critical role in schizophrenia (SZ). Among genes of neuronal plasticity there is Neuritin1 gene (NRN1), which has been associated with SZ, age at onset and differences in general cognitive performance in this disorder. However, little is known about the brain imaging correlates of NRN1 gene. We aimed: i) to investigate the association of NRN1 with schizophrenia-spectrum disorders (SZ-SD), exploring its role in age at onset through a family-based study, ii) to examine the brain functional correlates of NRN1 sequence variants through a neuroimaging genetics approach using a case-control design.MethodsA family-based association analysis was carried out with a sample of 588 individuals from 159 families (74 early onset / 85 adult onset) with an offspring with a diagnosis of SZ-SD. An independent sample consisting of 45 subjects (26 patients / 19 controls) was used to perform a case-control neuroimaging genetics analysis. DNA was extracted from blood/buccal mucosa samples and eleven Single Nucleotide Polymorphisms (SNPs) in NRN1 were genotyped. The linkage disequilibrium between the SNPs was estimated in the family-based sample with Haploview v4.1. Three haplotype blocks were defined: 1) rs2208870, rs12333117, rs582186, 2) rs645649, rs582262, 3) rs3763180, rs10484320, rs4960155, rs9379002, rs9405890, rs1475157. PLINK-v1.06 was used for the tabulation of possible individual haplotype phases and for the family-based association analyses (Transmission Disequilibrium Test). To explore the brain functional correlates of NRN1, the subjects belonging to case-control sample underwent a single MRI scanning session and performed a virtual reality spatial navigation task (Salgado-Pineda et al. 2016). The standard atlas provided in the FSL package was used to define three separate ROIs (left and right hippocampus and medial frontal region (mPFC)) and the mean value of activation per each subject was used to test the effect of each SNP/haplotypes by means of a linear regression. All the analyses were adjusted by age, sex and premorbid intelligence coefficient (IQ-TAP).ResultsTwo haplotypes including SNP4 and SNP5 (rs645649-rs582262) were associated with early onset SZ-SD: the haplotype CG was undertransmitted from parents to patients (p=0.011, OR (95%CI=0.08(0.01–0.71) - protective haplotype), while the haplotype GG showed an overtransmission trend (p=0.055, OR (95%CI=3.83 (1.40–10.48)). No effect was observed in the adult onset subsample.No differences between patients and controls were observed in the activation of the three ROIs. Within patients, an effect of the haplotype CG (SNP4-5) was detected in the mPFC: carriers of no copies of the protective haplotype showed a higher mean activation (n=15, mean(SD)=-1.17(17.37)) than individuals with at least one copy of the haplotype (n=9, mean(SD)=-21.19(21.94)) (⎕=-0.507 p=0.035).DiscussionFirst, our family-based results are consistent with evidence of a genetic association between NRN1 gene and SZ-SD and extend the knowledge on that NRN1 has a selective impact on early age at onset (Fatjó-Vilas et al. 2016). Second, our data suggest that NRN1 is involved in the regulation of the de-activation of mPFC in patients with SZ during a spatial navigation task. This result is of special interest since mPFC is an area included in the Default Mode Network (DMN) and alterations in this network have been highly documented in SZ patients during performance of different tasks (Pomarol-Clotet et al. 2008; Mannell et al. 2010; Salgado-Pineda et al. 2011).AcknowledgementsFundación Alicia Koplowitz.

Differential effect of disease-associated ST8SIA2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls

Brain white matter abnormalities are evident in individuals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of individuals with schizophrenia (n = 281) and healthy controls (n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype (p < 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with schizophrenia. The ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.

From child maltreatment to emerging adult problem drinking: Identification of a multilevel internalizing pathway among African American youth.

The present study tested the role of FKBP5 binding protein 5 (FKBP5) genetic variation in an internalizing pathway from child maltreatment to emerging adult problem drinking among a sample of African American youth (N = 280) followed prospectively from ages 11 to 20. Specifically, whether childhood internalizing symptoms and emerging adult tension reduction alcohol expectancies sequentially mediate the effect of child maltreatment on emerging adult problem drinking and whether FKBP5 moderates these associations were investigated. The results indicate that individuals with at least one copy of the FKBP5 CATT haplotype (minor alleles) are more vulnerable to traversing the hypothesized internalizing pathway of risk than individuals without this genotypic profile. Taken together our findings highlight the importance of FKBP5 genetic variation in the context of early adversity; support the role of two prospective sequential mediators of an internalizing pathway to problematic drinking, namely, childhood internalizing symptoms and emerging adult tension reduction alcohol expectancies; and identify a subgroup of maltreated children most susceptible to progressing along this less common pathway of risk.

Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk

BackgroundUse of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels. MethodsPremenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study. ResultsTwo copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6nmol/L, 95%CI: −61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis. ConclusionGenetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.

Association of the calpastatin genotypes, haplotypes, and SNPs with meat quality and fatty acid composition in two Iranian fat- and thin-tailed sheep breeds

This study was conducted to investigate the relationship between variation within Calpastatin (CAST) gene and meat quality and fatty acid profiles in fat-tailed (Chall) and thin-tailed (Zel) Iranian sheep breeds using PCR–SSCP, DNA sequence, and genotype, haplotype, and SNP effect analyses. Six previously identified SNPs including C24T, G62A, G65T, and T69- located in intron 5 and c.197A>T and c.282G>T localized in exon 6 were observed. These SNPs constituted six haplotypes of CAST-1, CAST-2, CAST-6, CAST-8, CAST-10, and CAST-11, corresponding to six genotypes of “B”, “C”, “D”, “F”, “I”, and “J”. Animals inheriting genotype “I” had lower value of shear force (P<0.03), concentration of palmitic acid (P<0.05), cholesterol (P<0.05), and n−6:n−3 ratio (P<0.02), and higher content of palmitoleic acid (P<0.04) compared to those inheriting the other genotypes. Also, animals containing one copy of CAST-10 haplotype showed lower value of shear force (P<0.005), lower n−6:n−3 ratio (P<0.02), higher concentration of palmitoleic acid (P<0.04) and total mono-unsaturated fatty acid (P<0.02) than those containing the other haplotypes. SNP effect analyses showed that three SNPs including G62A, G65T, and c.197A>T had significant effects on the content of some fatty acids and their selected ratios (P<0.05 to P<0.001), shear force (P=0.006 and P<0.001), and the cholesterol content of longissimus dorsi muscle (P<0.05). Overall, it seems that genotype “I”, haplotype CAST-10, the “AA” genotype of SNP G62A, and the “GT” genotype of G65T SNP were the most desirable genotypes and haplotype when selecting lambs in terms of both tenderness and fatty acid composition of meat, because selecting these genotypes and this haplotype would increase tenderness and proportion of healthy fatty acids, and also decrease proportion of harmful fatty acids of meat.

The interactive effects of child maltreatment and the FK506 binding protein 5 gene (FKBP5) on dissociative symptoms in adolescence.

The FK506 binding protein 5 gene (FKBP5) has been associated with susceptibility to pathogenic effects of childhood trauma including dissociative symptoms. This study examines the impact of maltreatment on dissociative tendencies in adolescence as moderated by the FKBP5 gene. Dissociative symptoms and variation within FKBP5 were assessed in a high-risk, low socioeconomic status community sample of 279 maltreated and 171 nonmaltreated adolescents. Following the assignment of haplotypes across four single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080), individuals with one or more copies of the CATT haplotype (N = 230) were grouped together and compared to individuals with zero copies of this haplotype (N = 185). Analyses of covariance were conducted to test hypotheses regarding the effects of developmental timing and the chronicity of maltreatment and the CATT haplotype. We found a significant interactive effect of timing/chronicity of maltreatment and the CATT haplotype on dissociative symptoms. Among adolescents who had no copies of the CATT haplotype, dissociative symptoms were higher for chronically maltreated adolescents who had an infancy onset compared to those who were not maltreated or whose maltreatment experience was either relatively less chronic or not started in infancy. The groups did not differ significantly among subjects who carry one or more copies of the CATT haplotype.

Inducible Nitric Oxide Synthase Promoter Haplotypes and Residential Traffic-Related Air Pollution Jointly Influence Exhaled Nitric Oxide Level in Children.

BackgroundExhaled nitric oxide (FeNO), a biomarker of airway inflammation, predicts asthma risk in children. We previously found that the promoter haplotypes in inducible nitric oxide synthase (NOS2) and exposure to residential traffic independently influence FeNO level. Because NOS2 is inducible by environmental exposures such as traffic-related exposure, we tested the hypothesis that common NOS2 promoter haplotypes modulate the relationship between residential traffic-related exposure and FeNO level in children.MethodsIn a cross-sectional population-based study, subjects (N = 2,457; 7–11 year-old) were Hispanic and non-Hispanic white children who participated in the Southern California Children’s Health Study and had FeNO measurements. For residential traffic, lengths of local roads within circular buffers (50m, 100m and 200m radii around homes) around the subjects’ homes were estimated using geographic information system (GIS) methods. We interrogated the two most common NOS2 promoter haplotypes that were found to affect FeNO level.ResultsThe relationship between local road lengths within 100m and 200m circular buffers and FeNO level varied significantly by one of the NOS2 promoter haplotypes (P-values for interaction between road length and NOS2 promoter haplotype = 0.02 and 0.03, respectively). In children who had ≤250m of local road lengths within 100m buffer around their homes, those with two copies of the haplotype had significantly lower FeNO (adjusted geometric mean = 11.74ppb; 95% confidence intervals (CI): 9.99 to 13.80) than those with no copies (adjusted geometric mean = 15.28ppb; 95% CI: 14.04 to 16.63) with statistically significant trend of lower FeNO level with increasing number of haplotype copy (P-value for trend = 0.002). In contrast, among children who had >250m of local road lengths within 100m buffer, FeNO level did not significantly differ by the haplotype copy-number (P-value for trend = 0.34). Similar interactive effects of this haplotype and local road lengths within 200m buffer on FeNO were also observed.ConclusionsHigher exposure from residential traffic nullifies the protective effect of one common NOS2 promoter haplotype on FeNO level. Regulation of traffic-related pollution may protect children’s respiratory health.

Analysis of DLA-DQB1 and polymorphisms in CTLA4 in Cocker spaniels affected with immune-mediated haemolytic anaemia.

BackgroundCocker spaniels are predisposed to immune-mediated haemolytic anaemia (IMHA), suggesting that genetic factors influence disease susceptibility. Dog leukocyte antigen (DLA) class II genes encode major histocompatibility complex (MHC) molecules that are involved in antigen presentation to CD4+ T cells. Several DLA haplotypes have been associated with autoimmune disease, including IMHA, in dogs, and breed specific differences have been identified. Cytotoxic T lymphocyte antigen 4 (CTLA4) is a critical molecule involved in the regulation of T-cell responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 promoter have been shown to be associated with several autoimmune diseases in humans and more recently with diabetes mellitus and hypoadrenocorticism in dogs. The aim of the present study was to investigate whether DLA-DQB1 alleles or CTLA4 promoter variability are associated with risk of IMHA in Cocker spaniels.ResultsThere were a restricted number of DLA-DQB1 alleles identified, with a high prevalence of DLA-DQB1*007:01 in both groups. A high prevalence of DLA-DQB1 homozygosity was identified, although there was no significant difference between IMHA cases and controls. CTLA4 promoter haplotype diversity was limited in Cocker spaniels, with all dogs expressing at least one copy of haplotype 8. There was no significant difference comparing haplotypes in the IMHA affected group versus control group (p = 0.23). Homozygosity for haplotype 8 was common in Cocker spaniels with IMHA (27/29; 93 %) and in controls (52/63; 83 %), with no statistically significant difference in prevalence between the two groups (p = 0.22).ConclusionsDLA-DQB1 allele and CTLA4 promoter haplotype were not found to be significantly associated with IMHA in Cocker spaniels. Homozygosity for DLA-DQB1*007:01 and the presence of CTLA4 haplotype 8 in Cocker spaniels might increase overall susceptibility to IMHA in this breed, with other genetic and environmental factors involved in disease expression and progression.

A spatial haplotype copying model with applications to genotype imputation.

Ever since its introduction, the haplotype copy model has proven to be one of the most successful approaches for modeling genetic variation in human populations, with applications ranging from ancestry inference to genotype phasing and imputation. Motivated by coalescent theory, this approach assumes that any chromosome (haplotype) can be modeled as a mosaic of segments copied from a set of chromosomes sampled from the same population. At the core of the model is the assumption that any chromosome from the sample is equally likely to contribute a priori to the copying process. Motivated by recent works that model genetic variation in a geographic continuum, we propose a new spatial-aware haplotype copy model that jointly models geography and the haplotype copying process. We extend hidden Markov models of haplotype diversity such that at any given location, haplotypes that are closest in the genetic-geographic continuum map are a priori more likely to contribute to the copying process than distant ones. Through simulations starting from the 1000 Genomes data, we show that our model achieves superior accuracy in genotype imputation over the standard spatial-unaware haplotype copy model. In addition, we show the utility of our model in selecting a small personalized reference panel for imputation that leads to both improved accuracy as well as to a lower computational runtime than the standard approach. Finally, we show our proposed model can be used to localize individuals on the genetic-geographical map on the basis of their genotype data.