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Harold Snieder - One of the best experts on this subject based on the ideXlab platform.

  • Genetic influence on early age related maculopathy a twin study
    Ophthalmology, 2002
    Co-Authors: Christopher J Hammond, Andrew R Webster, Alan C Bird, Clare Gilbert, Harold Snieder, Timothy D. Spector
    Abstract:

    OBJECTIVE: Age-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the Genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown. DESIGN: A classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins. PARTICIPANTS: Five hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined. METHODS: ARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 x 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood Genetic modeling to estimate the heritabilities of phenotypes graded. MAIN OUTCOME MEASURES: Prevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen >63 microm and > or =125 microm diameter, pigmentary changes and hard drusen ( or =20 in number); heritability of ARM and subphenotypes. RESULTS: The overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%-16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a Genetic Effect for phenotypes of ARM, soft drusen, pigmentary changes, and > or =20 hard drusen, although there was little Genetic Effect for scattered ( or =125 microm (57%) and > or =20 hard drusen (81%), with the latter being dominantly inherited. CONCLUSIONS: This study confirms a significant Genetic influence in ARM and suggests that future Genetic studies should examine phenotypes of large (> or =125 microm) soft drusen and > or =20 hard drusen, because these seem to be the most heritable components.

  • Genetic influence on early age related maculopathy a twin study
    Ophthalmology, 2002
    Co-Authors: Christopher J Hammond, Andrew R Webster, Alan C Bird, Clare Gilbert, Harold Snieder, Tim D Spector
    Abstract:

    Abstract Objective Age-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the Genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown. Design A classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins. Participants Five hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined. Methods ARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 × 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood Genetic modeling to estimate the heritabilities of phenotypes graded. Main outcome measures Prevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen >63 μm and ≥125 μm diameter, pigmentary changes and hard drusen ( Results The overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%–16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a Genetic Effect for phenotypes of ARM, soft drusen, pigmentary changes, and ≥20 hard drusen, although there was little Genetic Effect for scattered ( Conclusions This study confirms a significant Genetic influence in ARM and suggests that future Genetic studies should examine phenotypes of large (≥125 μm) soft drusen and ≥20 hard drusen, because these seem to be the most heritable components.

  • Genetic contribution to bone metabolism calcium excretion and vitamin d and parathyroid hormone regulation
    Journal of Bone and Mineral Research, 2001
    Co-Authors: David J Hunter, M De Lange, Harold Snieder, A J Macgregor, R Swaminathan, Rajesh V Thakker, Tim D Spector
    Abstract:

    A classical twin study was performed to assess the relative contribution of Genetic and environmental factors to bone metabolism, calcium homeostasis, and the hormones regulating them. It was examined further whether the Genetic Effect is menopause dependent. The subjects were 2136 adult twins (98.3% female): 384 monozygotic (MZ) and 684 dizygotic (DZ) twin pairs. The intraclass correlations were calculated, and maximum likelihood model fitting was used to estimate Genetic and environmental variance components. The intraclass correlations for all of the variables assessed were higher in MZ twin pairs. The heritabilities (95% CIs) obtained from model fitting for hormones regulating bone metabolism and calcium homeostasis were parathyroid hormone (PTH), 60% (54-65%); 25-hydroxyvitamin D [25(OH)D]; 43% (28-57%), 1,25-hydroxyvitamin D [1,25(OH)], 65% (53-74%); and vitamin D binding protein 62% (56-66%). The heritabilities (95% CIs) for markers of bone formation also were assessed; bone-specific alkaline phosphatase (BSAP), 74% (67-80%), and osteocalcin, 29% (14-44%); marker of bone resorption deoxypyridinoline (DPD), 58% (52-64%); and measure of calcium homeostasis 24 h urine calcium, creatinine (Cr), 52% (41-61%). The magnitude of Genetic influence differed with menopause for most variables. This study provides evidence for the importance of Genetic factors in determining bone resorption and formation, calcium excretion, and the hormones regulating these processes. It shows for the first time a clear Genetic Effect on bone resorption in premenopausal women and the regulation of PTH, vitamin D metabolism, and calcium excretion. The genes controlling bone hormones and markers are likely to be useful therapeutic and diagnostic targets.

  • genes control the cessation of a woman s reproductive life a twin study of hysterectomy and age at menopause
    The Journal of Clinical Endocrinology and Metabolism, 1998
    Co-Authors: Harold Snieder, A J Macgregor, Timothy D. Spector
    Abstract:

    A classical twin study was performed to assess the extent to which Genetic factors explain individual differences in age at menopause and (indications for) hysterectomy. It was further examined whether a Genetic Effect on the timing of the menopause was mediated through a Genetic Effect on age at menarche. The subjects were 275 monozygotic and 353 dizygotic female twin pairs. Maximum likelihood model fitting was used to estimate Genetic and environmental variance components, Kaplan-Meier survival analysis was used to account for censored data, and the Cox proportional hazards model was used to adjust for potential confounders. A model specifying additive Genetic and unique environmental factors showed the best fit to the data, yielding a heritability (h2) for age at menopause of 63%. The significance of the Genetic Effect was confirmed by the survival analysis and was not affected by adjustment for confounders. Both early and late menopause were found to be significantly influenced by Genetic factors. Hys...

Ryk Ward - One of the best experts on this subject based on the ideXlab platform.

  • linkage and association analysis of angiotensin i converting enzyme ace gene polymorphisms with ace concentration and blood pressure
    American Journal of Human Genetics, 2001
    Co-Authors: Nourdine Bouzekri, Colin A Mckenzie, Lorraine Southam, Adebowale Adeyemo, Guangjie Chen, Amy Luke, Richard S. Cooper, Ryk Ward
    Abstract:

    Considerable effort has been expended to determine whether the gene for angiotensin I–converting enzyme (ACE) confers susceptibility to cardiovascular disease. In this study, we genotyped 13 polymorphisms in the ACE gene in 1,343 Nigerians from 332 families. To localize the Genetic Effect, we first performed linkage and association analysis of all the markers with ACE concentration. In multipoint variance-component analysis, this region was strongly linked to ACE concentration (maximum LOD score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE ( P

  • linkage and association analysis of angiotensin i converting enzyme ace gene polymorphisms with ace concentration and blood pressure
    American Journal of Human Genetics, 2001
    Co-Authors: Nourdine Bouzekri, Colin A Mckenzie, Lorraine Southam, Adebowale Adeyemo, Guangjie Chen, Amy Luke, Richard S. Cooper, Robert C Elston, Ryk Ward
    Abstract:

    Considerable effort has been expended to determine whether the gene for angiotensin I–converting enzyme (ACE) confers susceptibility to cardiovascular disease. In this study, we genotyped 13 polymorphisms in the ACE gene in 1,343 Nigerians from 332 families. To localize the Genetic Effect, we first performed linkage and association analysis of all the markers with ACE concentration. In multipoint variance-component analysis, this region was strongly linked to ACE concentration (maximum LOD score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE ( P

Christoph Lange - One of the best experts on this subject based on the ideXlab platform.

  • a doubly robust test for gene environment interaction in family based studies of affected offspring
    Biostatistics, 2010
    Co-Authors: Beatrijs Moerkerke, Stijn Vansteelandt, Christoph Lange
    Abstract:

    We develop a locally efficient test for (multiplicative) gene-environment interaction in family studies that collect genotypic information and environmental exposures for affected offspring along with genotypic information for their parents or relatives. The proposed test does not require modeling the Effects of environmental exposures and is doubly robust in the sense of being valid if either a model for the main Genetic Effect holds or a model for the expected environmental exposure (given the offspring affection status and parental mating types) but not necessarily both. It extends the FBAT-I to allow for missing parental mating types and families of arbitrary size. Simulation studies and the analysis of an Alzheimer's disease study confirm the adequate performance of the proposed test.

  • screening and replication using the same data set testing strategies for family based studies in which all probands are affected
    PLOS Genetics, 2008
    Co-Authors: Christoph Lange, Amy Murphy, Scott T Weiss
    Abstract:

    For genome-wide association studies in family-based designs, we propose a powerful two-stage testing strategy that can be applied in situations in which parent-offspring trio data are available and all offspring are affected with the trait or disease under study. In the first step of the testing strategy, we construct estimators of Genetic Effect size in the completely ascertained sample of affected offspring and their parents that are statistically independent of the family-based association/transmission disequilibrium tests (FBATs/TDTs) that are calculated in the second step of the testing strategy. For each marker, the Genetic Effect is estimated (without requiring an estimate of the SNP allele frequency) and the conditional power of the corresponding FBAT/TDT is computed. Based on the power estimates, a weighted Bonferroni procedure assigns an individually adjusted significance level to each SNP. In the second stage, the SNPs are tested with the FBAT/TDT statistic at the individually adjusted significance levels. Using simulation studies for scenarios with up to 1,000,000 SNPs, varying allele frequencies and Genetic Effect sizes, the power of the strategy is compared with standard methodology (e.g., FBATs/TDTs with Bonferroni correction). In all considered situations, the proposed testing strategy demonstrates substantial power increases over the standard approach, even when the true Genetic model is unknown and must be selected based on the conditional power estimates. The practical relevance of our methodology is illustrated by an application to a genome-wide association study for childhood asthma, in which we detect two markers meeting genome-wide significance that would not have been detected using standard methodology.

Adebowale Adeyemo - One of the best experts on this subject based on the ideXlab platform.

Timothy D. Spector - One of the best experts on this subject based on the ideXlab platform.

  • Genetic influence on early age related maculopathy a twin study
    Ophthalmology, 2002
    Co-Authors: Christopher J Hammond, Andrew R Webster, Alan C Bird, Clare Gilbert, Harold Snieder, Timothy D. Spector
    Abstract:

    OBJECTIVE: Age-related macular degeneration (AMD) is the most common cause of blindness in industrialized countries. There has been considerable interest in the Genetics of early age-related maculopathy (ARM) and AMD, because they have phenotypes similar to inherited diseases where mutations have been identified, but the heritability of ARM and AMD is unknown. DESIGN: A classical twin study was performed to compare the concordance in monozygotic (MZ) and dizygotic (DZ) twins in an unselected sample of female volunteer twins. PARTICIPANTS: Five hundred six twin pairs, 226 MZ and 280 DZ, with a mean age of 62 years, were examined. METHODS: ARM was graded from stereoscopic macular photographs of 501 of the twin pairs (99%) according to the International ARM Epidemiologic Study Group grading system. The casewise concordance was calculated for twin pairs from 2 x 2 contingency tables of affected/unaffected twins, and these tables were used in maximum likelihood Genetic modeling to estimate the heritabilities of phenotypes graded. MAIN OUTCOME MEASURES: Prevalence of ARM; concordance in MZ and DZ twins of the phenotypes of ARM, soft drusen >63 microm and > or =125 microm diameter, pigmentary changes and hard drusen ( or =20 in number); heritability of ARM and subphenotypes. RESULTS: The overall prevalence of ARM was 14.6% (95% confidence interval [CI], 12.4%-16.8%). The concordance for ARM in MZ twins was 0.37 compared with 0.19 in DZ twins, suggesting a role for genes. Modeling confirmed a Genetic Effect for phenotypes of ARM, soft drusen, pigmentary changes, and > or =20 hard drusen, although there was little Genetic Effect for scattered ( or =125 microm (57%) and > or =20 hard drusen (81%), with the latter being dominantly inherited. CONCLUSIONS: This study confirms a significant Genetic influence in ARM and suggests that future Genetic studies should examine phenotypes of large (> or =125 microm) soft drusen and > or =20 hard drusen, because these seem to be the most heritable components.

  • genes control the cessation of a woman s reproductive life a twin study of hysterectomy and age at menopause
    The Journal of Clinical Endocrinology and Metabolism, 1998
    Co-Authors: Harold Snieder, A J Macgregor, Timothy D. Spector
    Abstract:

    A classical twin study was performed to assess the extent to which Genetic factors explain individual differences in age at menopause and (indications for) hysterectomy. It was further examined whether a Genetic Effect on the timing of the menopause was mediated through a Genetic Effect on age at menarche. The subjects were 275 monozygotic and 353 dizygotic female twin pairs. Maximum likelihood model fitting was used to estimate Genetic and environmental variance components, Kaplan-Meier survival analysis was used to account for censored data, and the Cox proportional hazards model was used to adjust for potential confounders. A model specifying additive Genetic and unique environmental factors showed the best fit to the data, yielding a heritability (h2) for age at menopause of 63%. The significance of the Genetic Effect was confirmed by the survival analysis and was not affected by adjustment for confounders. Both early and late menopause were found to be significantly influenced by Genetic factors. Hys...