Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Some Atypical and Rare Sickle Cell Gene Haplotypes in Populations of Andhra Pradesh, India

We have investigated the clinical, hematological, and molecular genetic characteristics of sickle cell anemia patients from 6 populations of Andhra Pradesh, South India. Of 72 sickle cell chromosomes (HBB*S) 60 belong to characteristic Arab-Indian haplotypes, 6 to variant Arab-Indian haplotypes, 1 to a Bantu haplotype, 2 to a Cameroon haplotype, and 3 to rare haplotypes. This is the first report of a Bantu haplotype in an Indian population. Some information on haplotype characteristics of normal chromosomes (HBB*A) is also presented. The average hemoglobin level was 7.3 g% and mean fetal hemoglobin (HbF) level was 12.6%. The higher HbF levels corroborate earlier observations in sickle cell homozygotes from India. Clinical investigations have revealed splenomegaly and painful crises as the most common features in these patients

Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients.

Item does not contain fulltextHeterogeneous mutations in factor IX (FIX) gene cause haemophilia B and a large number of mutations have been characterized. However, reports on gene defects among Indian haemophilia B patients are rare despite a high estimate of such patients in the country. We report identification of 22 independent mutations including five novel mutations in 24 unrelated patients. The novel gene defects include two point mutations, two deletions and one insertion of a LINE 1 element. Majority of the mutations (14 of 24) occurred on the same haplotype background, but do not suggest any founder effect. Direct identification of mutations can be utilized to perform the carrier detection and prenatal diagnosis, especially in families with isolated patients

Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis

Background: disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established.Methods: we studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C?T) by instrumental variable and triangulation analysis, separately and using meta-analysis.Results: median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642?g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871?g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration—PMNS: –22?g/SD [95% confidence interval (CI): (–50, 5), adjusted for gestational age and offspring gender]; Parthenon: –57?g (–92, –21); meta-analysis: –40?g (–62, –17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: –46?g (–102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: –78?g (–170, 15); meta-analysis: –61?g (–111, –10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight.Conclusions: our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growt

Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism

BackgroundMounting evidence suggests that nutritional exposures during pregnancy influence the fetal epigenome, and that these epigenetic changes can persist postnatally, with implications for disease risk across the life course.MethodsWe review human intergenerational studies using a three-part search strategy. Search 1 investigates associations between preconceptional or pregnancy nutritional exposures, focusing on one-carbon metabolism, and offspring DNA methylation. Search 2 considers associations between offspring DNA methylation at genes found in the first search and growth-related, cardiometabolic and cognitive outcomes. Search 3 isolates those studies explicitly linking maternal nutritional exposure to offspring phenotype via DNA methylation. Finally, we compile all candidate genes and regions of interest identified in the searches and describe their genomic locations, annotations and coverage on the Illumina Infinium Methylation beadchip arrays.ResultsWe summarize findings from the 34 studies found in the first search, the 31 studies found in the second search and the eight studies found in the third search. We provide details of all regions of interest within 45 genes captured by this review.ConclusionsMany studies have investigated imprinted genes as priority loci, but with the adoption of microarray-based platforms other candidate genes and gene classes are now emerging. Despite a wealth of information, the current literature is characterized by heterogeneous exposures and outcomes, and mostly comprise observational associations that are frequently underpowered. The synthesis of current knowledge provided by this review identifies research needs on the pathway to developing possible early life interventions to optimize lifelong health

Associations of genetic variants in/near body mass index-associated genes with type 2 diabetes: A systematic meta-analysis.

ObjectiveGenome-wide association studies have identified many obesity/body mass index (BMI)-associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI-associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk. MethodsWe retrieved published literature from PubMed and Embase. The pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed- or random-effect models. ResultsIn the meta-analysis of 42 studies for 11 obesity/BMI-associated loci, we observed a statistically significant association of the FTO rs9939609 polymorphism (66425 T2D cases/239689 normoglycaemic subjects; P=100x10(-41)) and six other variants with T2D risk (17915 T2D cases/27531 normoglycaemic individuals: n=40629-130001; all P&lt;0001 for SH2B1 rs7498665, FAIM2 rs7138803, TMEM18 rs7561317, GNPDA2 rs10938397, BDNF rs925946 and NEGR1 rs2568958). After adjustment for BMI, the association remained statistically significant for four of the seven variants (all P&lt;005 for FTO rs9939609, SH2B1 rs7498665, FAIM2 rs7138803, GNPDA2 rs10938397). Subgroup analysis by ethnicity demonstrated similar results. ConclusionsThis meta-analysis indicates that several BMI-associated variants are significantly associated with T2D risk. Some variants increase the T2D risk independent of obesity, while others mediate this risk through obesity