89 results found
Maude H, Davidson M, Charitakis N, et al., 2019, NUMT confounding biases mitochondrial heteroplasmy calls in favor of the reference allele, Frontiers in Cell and Developmental Biology, Vol: 7, ISSN: 2296-634X
Homology between mitochondrial DNA (mtDNA) and nuclear DNA of mitochondrial origin (nuMTs) causes confounding when aligning short sequence reads to the reference human genome, as the true sequence origin cannot be determined. Using a systematic in silico approach, we here report the impact of all potential mitochondrial variants on alignment accuracy and variant calling. A total of 49,707 possible mutations were introduced across the 16,569bp reference mitochondrial genome (16,569 x 3 alternative alleles), one variant at-at-time. The resulting in silico fragmentation and alignment to the entire reference genome (GRCh38) revealed preferential mapping of mutated mitochondrial fragments to nuclear loci, as variants increased loci similarity to nuMTs, for a total of 807, 362 and 41 variants at 333, 144 and 27 positions when using 100bp, 150bp and 300bp single end fragments. We subsequently modelled these affected variants at 50% heteroplasmy and carried out variant calling, observing bias in the reported allele frequencies in favor of the reference allele. Four variants (chrM:6023A, chrM:4456T, chrM:5147A and chrM:7521A) including a possible hypertension factor, chrM:4456T, caused 100% loss of coverage at the mutated position (with all 100bp single-end fragments aligning to homologous, nuclear positions instead of chrM), rendering these variants undetectable when aligning to the entire reference genome. Furthermore, four mitochondrial variants reported to be pathogenic were found to cause significant loss of coverage and select Haplogroup-defining SNPs were shown to exacerbate the loss of coverage caused by surrounding variants. Increased fragment length and use of paired-end reads both improved alignment accuracy.
Dalmia A, Dib M-J, Maude H, et al., 2019, A genetic epidemiological study in British adults and older adults shows a high heritability of the combined indicator of vitamin B12 status (cB12) and connects B12 status with utilization of mitochondrial substrates and energy metabolism, The Journal of Nutritional Biochemistry, Vol: 70, Pages: 156-163, ISSN: 0955-2863
Vitamin B12 deficiency is common among older adults. However, the most commonly used marker of deficiency, total serum vitamin B12 (B12), is not sensitive enough to diagnose true deficiency in a significant proportion of the population. The combined indicator of B12 status (cB12), formulated as a composite score of various biomarkers of vitamin B12 status (which also accounts for low folate status and age) has been shown to offer a more robust and powerful test to diagnose B12 deficiency.There are no epidemiological studies of cB12 variability in older adults. We carried out a twin study to characterize the relative contribution of heritable (h2) and environmental factors to the observed variability in cB12 score in an adult and older adult population (n=378). Furthermore, we tested for association between variability in cB12 and candidate polymorphisms and genes previously associated with B12 biomarker levels characterized in silico the mechanism linking the genetic variants and cB12 variability.We found the variability in cB12 and its constituents to be highly heritable (h2=55%–64%). The single nucleotide polymorphism rs291466 in HIBCH, previously associated with variation in MMA, was significantly associated with cB12 (R2=5%, P=5E-04). Furthermore, variants in MTRR, MMAB and MUT, underlying inborn errors of B12 metabolism, were nominally associated with variation in cB12. Pathway accompanied by expression quantitative trait loci analysis revealed that HIBCH rs291466 influences the concentration of MMA via the valine degradation pathway.Our study provides etiological insight into how B12 deficiency can manifest into impaired mitochondrial function through perturbations in mitochondrial “fuel” usage.
Parmar P, Lowry E, Cugliari G, et al., 2018, Association of maternal prenatal smoking GFI1-locus and cardiometabolic phenotypes in 18,212 adults, EBioMedicine, Vol: 38, Pages: 206-216, ISSN: 2352-3964
BackgroundDNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health.MethodsWe meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pressure (BP).FindingsLower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10−7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10−8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels.InterpretationEpigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors.
Andrew T, Nash A, Mandaviya P, et al., 2018, Interaction between plasma homocysteine and the MTHFR c.677C>T polymorphism is associated with site-specific changes in DNA methylation in humans, The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, ISSN: 0892-6638
One-carbon metabolism provides a direct link among dietary folate/vitamin B12 exposure, the activity of the enzyme methylenetetrahydrofolate reductase (MTHFR), and epigenetic regulation of the genome via DNA methylation. Previously, it has been shown that the common c.677C > T polymorphism in MTHFR influences global DNA methylation status through a direct interaction with folate status and (indirectly) with total homocysteine (tHcy) levels. To build on that and other more-recent observations that have further highlighted associations among MTHFR c.677C > T, tHcy, and aberrations in DNA methylation, we investigated whether the interaction between mildly elevated plasma tHcy and the c.677C > T polymorphism is associated with site-specific changes in DNA methylation in humans. We used data on plasma tHcy levels, c.677C > T polymorphism, and site-specific DNA methylation levels for a total of 915 white women and 335 men from the TwinsUK registry (n = 610) and the Rotterdam study (n = 670). We performed methylome-wide association analyses in each cohort to model the interaction between levels of tHcy and c.677C > T genotypes on DNA methylation β values. Our meta-analysis identified 13 probes significantly associated with rs1801133 × tHcy levels [false-discovery rate (FDR) < 0.05]. The most significant associations were with a cluster of probes at the AGTRAP–MTHFR–NPPA/B gene locus on chromosome 1 (FDR = 1.3E−04), with additional probes on chromosomes 2, 3, 4, 7, 12, 16, and 19. Our top 2 hits on chromosome 1 were functionally associated with variability in expression of the TNF receptor superfamily member 8 (TNFRSF8) gene/locus on that chromosome. This is the first study, to our knowledge, to provide a direct link between perturbations in 1-carbon metabolism, through an interaction of tHcy and the activity of MTHFR enzyme on epigenetic regulation of the genome via DNA methylation.—Nash, A. J., Mandaviya, P. R., Dib, M.
Lau W, Andrew T, Maniatis N, 2017, High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 100, Pages: 803-816, ISSN: 0002-9297
Direk K, Lau W, Small KS, et al., 2014, ABCC5 Transporter is a Novel Type 2 Diabetes Susceptibility Gene in European and African American Populations, Annals of Human Genetics, Vol: 78, Pages: 333-344
Numerous functional studies have implicated PARL in relation to type 2 diabetes (T2D). We hypothesised that conflicting human association studies may be due to neighbouring causal variants being in linkage disequilibrium (LD) with PARL. We conducted a comprehensive candidate gene study of the extended LD genomic region that includes PARL and transporter ABCC5 using three data sets (two European and one African American), in relation to healthy glycaemic variation, visceral fat accumulation and T2D disease.We observed no evidence for previously reported T2D association with Val262Leu or PARL using array and fine-map genomic and expression data. By contrast, we observed strong evidence of T2D association with ABCC5 (intron 26) for European and African American samples (P = 3E−07) and with ABCC5 adipose expression in Europeans [odds ratio (OR) = 3.8, P = 2E−04]. The genomic location estimate for the ABCC5 functional variant, associated with all phenotypes and expression data (P = 1E−11), was identical for all samples (at Chr3q 185,136 kb B36), indicating that the risk variant is an expression quantitative trait locus (eQTL) with increased expression conferring risk of disease. That the association with T2D is observed in populations of disparate ancestry suggests the variant is a ubiquitous risk factor for T2D.
Ahmadi KR, Andrew T, 2014, Opportunism: a panacea for implementation of whole-genome sequencing studies in nutrigenomics research?, GENES AND NUTRITION, Vol: 9, ISSN: 1555-8932
Andrew T, Gill R, Gillham-Nasenya I, et al., 2013, Unravelling the basis of variability in cobalamin levels in the general population, BRITISH JOURNAL OF NUTRITION, Vol: 110, Pages: 1672-1679, ISSN: 0007-1145
Direk K, Cecelja M, Astle W, et al., 2013, The relationship between DXA-based and anthropometric measures of visceral fat and morbidity in women, BMC CARDIOVASCULAR DISORDERS, Vol: 13, ISSN: 1471-2261
Lopes MC, Hysi PG, Verhoeven VJM, et al., 2013, Identification of a Candidate Gene for Astigmatism, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 54, Pages: 1260-1267, ISSN: 0146-0404
Leschziner GD, Coffey AJ, Andrew T, et al., 2011, Q8IYL2 is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS), EPILEPSY RESEARCH, Vol: 96, Pages: 109-115, ISSN: 0920-1211
Andrew T, Calloway CD, Stuart S, et al., 2011, A Twin Study of Mitochondrial DNA Polymorphisms Shows that Heteroplasmy at Multiple Sites Is Associated with mtDNA Variant 16093 but Not with Zygosity, PLOS ONE, Vol: 6, ISSN: 1932-6203
Fahy SJ, Sun C, Zhu G, et al., 2011, The Relationship between Retinal Arteriolar and Venular Calibers Is Genetically Mediated, and Each Is Associated with Risk of Cardiovascular Disease, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 52, Pages: 975-981, ISSN: 0146-0404
Cotlarciuc I, Andrew T, Dew T, et al., 2011, The Basis of Differential Responses to Folic Acid Supplementation, JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS, Vol: 4, Pages: 99-109, ISSN: 1661-6499
Nettleton JA, McKeown NM, Kanoni S, et al., 2010, Interactions of Dietary Whole-Grain Intake With Fasting Glucose- and Insulin-Related Genetic Loci in Individuals of European Descent A meta-analysis of 14 cohort studies, DIABETES CARE, Vol: 33, Pages: 2684-2691, ISSN: 0149-5992
Nettleton JA, McKeown NM, Kanoni S, et al., 2010, Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies., Diabetes Care, Vol: 33, Pages: 2684-2691, ISSN: 0149-5992
OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
Ikram MK, Sim X, Jensen RA, et al., 2010, Correction: Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo, PLoS Genetics, Vol: 6
Ikram MK, Sim X, Jensen RA, et al., 2010, Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo., PLOS Genetics, Vol: 6, ISSN: 1553-7390
There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular dis
Hysi PG, Young TL, Mackey DA, et al., 2010, A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25, NATURE GENETICS, Vol: 42, Pages: 902-+, ISSN: 1061-4036
Carbonaro F, Andrew T, Mackey DA, et al., 2010, Comparison of three methods of intraocular pressure measurement and their relation to central corneal thickness, EYE, Vol: 24, Pages: 1165-1170, ISSN: 0950-222X
Macgregor S, Hewitt AW, Hysi PG, et al., 2010, Genome-wide association identifies ATOH7 as a major gene determining human optic disc size, HUMAN MOLECULAR GENETICS, Vol: 19, Pages: 2716-2724, ISSN: 0964-6906
Rakyan VK, Down TA, Maslau S, et al., 2010, Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains, GENOME RESEARCH, Vol: 20, Pages: 434-439, ISSN: 1088-9051
Andrew T, 2010, The genetic epidemiology of osteoporosis using intermediate phenotypes measured in healthy aging female twins.
Carbonaro F, Andrew T, Mackey DA, et al., 2009, Repeated Measures of Intraocular Pressure Result in Higher Heritability and Greater Power in Genetic Linkage Studies, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 50, Pages: 5115-5119, ISSN: 0146-0404
Kettunen J, Perola M, Martin NG, et al., 2009, Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci, INTERNATIONAL JOURNAL OF OBESITY, Vol: 33, Pages: 1235-1242, ISSN: 0307-0565
Jun G, Guo H, Klein BEK, et al., 2009, EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans, PLOS GENETICS, Vol: 5, ISSN: 1553-7404
Rahmioglu N, Andrew T, Cherkas L, et al., 2009, Epidemiology and Genetic Epidemiology of the Liver Function Test Proteins, PLOS ONE, Vol: 4, ISSN: 1932-6203
Lopes MC, Andrew T, Carbonaro F, et al., 2009, Estimating Heritability and Shared Environmental Effects for Refractive Error in Twin and Family Studies, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol: 50, Pages: 126-131, ISSN: 0146-0404
Zhai G, Andrew T, Kato BS, et al., 2009, Genetic and environmental determinants on bone loss in postmenopausal Caucasian women: a 14-year longitudinal twin study, Osteoporos.Int., Vol: 20, Pages: 949-953, ISSN: 1433-2965
SUMMARY: This longitudinal twin study documented that genetic factors explain 44-56% of the between-individual variance in bone loss at femoral neck, lumbar spine, and forearm in postmenopausal Caucasian women, providing a rationale for identifying the specific genes involved. INTRODUCTION: Although there is a significant genetic effect on peak BMD, until recently, no substantive studies on heritability of bone loss in human were available. The aim of the study was to estimate the heritability of the bone loss at multiple sites in postmenopausal Caucasian women. METHODS: Postmenopausal female monozygotic (MZ) and dizygotic (DZ) twins aged 40 or above at baseline were selected from the TwinsUK registry and followed up for an average of 8 years (range 5-14 years). All twins were noncurrent hormone replacement therapy users and not on any osteoporosis treatment. They had dual-energy X-ray absorptiometry (DXA) scans of their hip, lumbar spine, and forearm several times (range 2-9) during the follow-up period. Individual bone losses at femoral neck, lumbar spine, and forearm were estimated by linear regression modeling. Structural equation modeling was utilized to estimate the heritability of the bone loss. RESULTS: A total of 712 postmenopausal Caucasian female twins (152 MZ and 204 DZ pairs) were included. MZ twins were older and had slightly lower BMD at all sites than DZ twins. DZ twins had slightly higher bone loss at lumbar spine, but similar at femoral neck and forearm compared to MZ twins. Intraclass correlation coefficients (ICC) for the bone loss at all sites were significantly higher in MZ than DZ twin pairs (p = 0.0045, 0.0003, and 0.0007 for femoral neck, lumbar spine, and forearm, respectively), indicating a significant genetic influence on bone loss at these sites. After adjustment for age at baseline and weight change during the follow-up, the heritability estimate was 47% (95% CI 27-63%) for bone loss at femoral neck, 44% (95% CI 27-58%) for lumbar spine
Andrew T, Maniatis N, Carbonaro F, et al., 2008, Identification and Replication of Three Novel Myopia Common Susceptibility Gene Loci on Chromosome 3q26 using Linkage and Linkage Disequilibrium Mapping, PLOS GENETICS, Vol: 4, ISSN: 1553-7390
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