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PubMed1995

Plasma HDL cholesterol, triglycerides, and adiposity. A quantitative genetic test of the conjoint trait hypothesis in the San Antonio Family Heart Study.

BACKGROUND: The conjoint trait hypothesis proposes that combined low HDL cholesterol (HDL-C) and high triglyceride (TG) levels represent a single, inherited phenotype that adiposity may influence in an unspecified manner. We conducted formal statistical genetic tests of the conjoint trait hypothesis and the relation of the conjoint trait to adiposity using data for 569 subjects in 25 pedigrees from the San Antonio Family Heart Study. METHODS AND RESULTS: We conducted multivariate genetic analyses to detect the effects of genes and environmental factors on variation in plasma concentrations of HDL-C and TG, fat mass (as percent body weight [FM%], determined by bioelectric impedance), and body mass index (BMI). We used maximum-likelihood methods to simultaneously estimate the phenotypic means and SDs, heritabilities (h2), effects of sex, age-by-sex, eight dietary and medical covariates, and genetic and environmental correlations. Likelihood ratio tests disclosed significant heritabilities (P < .001) for all traits (h2HDL-C = 0.55, h2TG = 0.53, h2FM% = 0.37, h2BMI = 0.44) but significant genetic correlations (P < .001), indicating pleiotropy, between two trait pairs only: HDL-C and TG (PG = -0.52) and fat mass and BMI (PG = 0.86). We obtained significant environmental correlations between all trait pairs except HDL-C and BMI (P > .05). CONCLUSIONS: Both shared genes (pleiotropy) and shared environmental factors contribute to the commonly observed inverse phenotypic association between plasma levels of HDL-C and TG. Rather than low HDL-C and high TG being a single, genetically transmissible entity, it is the inverse relation between these two phenotypes throughout their normal ranges of variation as well as at the extremes that is influenced by shared genes and shared environments. However, common environmental factors, not shared genes, account for reported associations of plasma HDL-C and TG levels with measures of adiposity.

Adipose Tissue↗

PubMed2006

Amyotrophic lateral sclerosis as a complex genetic disease.

In complex diseases like ALS, there are multiple genetic and environmental factors all contributing to disease liability. The genetic factors causing susceptibility to developing ALS can be considered a spectrum from single genes with large effect sizes causing classical Mendelian ALS, to genes of smaller effect, producing apparently sporadic disease. We examine the statistical genetic principles that underpin this model and review what is known about ALS as a disease with complex genetics.

Age of Onset↗

PubMed2005

Permutation based methods for comparing quality of life between observed treatments.

Quality of life is becoming an important outcome for the comparison of aggressive therapies. To measure quality of life (QOL), questionnaires have been designed that ask patients about symptoms and functionality in several aspects of daily life. Primary analyses of such questionnaires typically focus on a summary statistic, such as a sum score or a single global question. This avoids inflated type I errors or loss of power due to multiple testing of individual items. In return, specific questions and answers that initially mattered to the patient may unfortunately get buried. To avoid reduced specificity and interpretability for both patients and physicians, we propose to also analyse all original questions. In this paper, we seek to detect items of the QOL questionnaire that differ significantly over observed treatments even in the face of multiple testing. We sequentially build a model that combines features which additionally discriminate between treatments. To achieve this, we draw on insights gained in the field of statistical genetics where one is often confronted with a vast amount of predictors, e.g. of a genotypic nature. Specifically, we adopt a permutation based approach to evaluate the null distribution of the maximum of many correlated test statistics and use it to build a regression model that explains QOL differences between treatment arms. We apply the new methodology to analyse QOL data in an observational study of four different treatments of breast cancer. We discover that a single question captures most of the observed treatment differences in this population.

Belgium↗

PubMedDate not supplied

Genetics of human body size and shape: body proportions and indices.

BACKGROUND: The study of the genetic component in morphological variables such as body height and weight, head and chest circumference, etc. has a rather long history. However, only a few studies investigated body proportions and configuration. AIM: The major aim of the present study was to evaluate the extent of the possible genetic effects on the inter-individual variation of a number of body configuration indices amenable to clear functional interpretation. SUBJECTS AND METHODS: Two ethnically different pedigree samples were used in the study: (1) Turkmenians (805 individuals) from Central Asia, and (2) Chuvasha (732 individuals) from the Volga riverside, Russian Federation. To achieve the aim of the present study we proposed three new indices, which were subjected to a statistical-genetic analysis using modified version of "FISHER" software. The proposed indices were: (1) an integral index of torso volume (IND#1), an index reflecting a predisposition of body proportions to maintain a balance in a vertical position (IND#2), and an index of skeletal extremities volume (IND#3). Additionally, the first two principal factors (PF1 and PF2) obtained on 19 measurements of body length and breadth were subjected to genetic analysis. Variance decomposition analysis that simultaneously assess the contribution of gender, age, additive genetic effects and effects of environment shared by the nuclear family members, was applied to fit variation of the above three indices, and PF1 and PF2. RESULTS: The raw familial correlation of all study traits and in both samples showed: (1) all marital correlations did not differ significantly from zero; (2) parent-offspring and sibling correlations were all positive and statistically significant. The parameter estimates obtained in variance analyses showed that from 40% to 75% of inter-individual variation of the studied traits (adjusted for age and sex) were attributable to genetic effects. For PF1 and PF2 in both samples, and for IND#2 (in Chuvasha pedigrees), significant common sib environmental effects were also detectable. CONCLUSION: Genetic factors substantially influence inter-individual differences in body shape and configuration in two studied samples. However, further studies are needed to clarify the extent of pleiotropy and epigenetic effects on various facets of the human physique.

Adolescent↗

PubMedDate not supplied

The next challenge for psychiatric genetics: characterizing the risk associated with identified genes.

BACKGROUND: As advances in genetics further our ability to identify genes influencing psychiatric disorders, the next challenge facing psychiatric genetics is to characterize the risk associated with specific genetic variants in order to better understand how these susceptibility genes are involved in the pathways leading to illness. METHODS: To further this goal, findings from behavior genetic analyses about how genetic influences act can be used to guide hypothesis testing about the effects associated with specific genes. RESULTS: Using the phenotype of alcohol dependence as an example, this paper provides an overview of how the integration of behavioral and statistical genetics can advance our knowledge about the genetics of psychiatric disorders. Areas currently being investigated in behavior genetics include careful delineation of phenotypes, to examine the heritability of various aspects of normal and abnormal behavior; developmental changes in the nature and magnitude of genetic and environmental effects; the extent to which different behaviors are influenced by common genes; and different forms of gene-environment correlation and interaction. CONCLUSIONS: Understanding how specific genes are involved in these processes has the potential to significantly enhance our understanding of the development of psychiatric disorders.

Alcoholism↗

PubMed2026

Human skin microbiota and postpartum depression: A bidirectional Mendelian randomization study.

Postpartum depression (PPD) is a common mental health disorder after childbirth. Although microbiome research in PPD has mainly focused on the gut, the role of skin microbiota remains unclear. We used Mendelian randomization (MR) to assess potential causal associations between skin microbiota and PPD. A bidirectional 2-sample MR analysis used genome-wide association study (GWAS) summary statistics. Genetic instruments for skin microbial features were obtained from a published skin microbiota GWAS, and PPD data were derived from 67,205 mothers (7604 cases, 59,601 controls). Instruments were selected at P <1 × 10-5, linkage disequilibrium-clumped, harmonized, and filtered for weak instruments (F statistic <10). Because this microbiome threshold is exploratory, Benjamini-Hochberg false discovery rate correction was applied within taxonomic levels. The inverse-variance weighted method was primary, complemented by weighted median and mode-based methods. Heterogeneity, pleiotropy, and outliers were assessed using Cochran Q, MR-Egger intercept, and MR-PRESSO. Three skin microbial taxa showed nominal associations with PPD. Higher genetically predicted Acinetobacter on the dorsal forearm (dry skin; 9 single nucleotide polymorphisms [SNPs]; mean F = 22.12) and Proteobacteria in the antecubital fossa (moist skin; 6 SNPs; mean F = 23.44) were associated with increased PPD risk, whereas Betaproteobacteria in the antecubital fossa (11 SNPs; mean F = 21.54) was associated with decreased risk. Associations were directionally consistent, with no substantial heterogeneity or horizontal pleiotropy. After multiple-testing assessment, the findings were exploratory rather than definitive. Reverse MR did not support an effect of PPD on the identified skin microbiota. This MR study provides exploratory genetic evidence linking specific skin microbial features to PPD risk. The findings extend microbiota-related hypotheses beyond the gut microbiome but require validation in larger microbiome GWAS datasets, longitudinal cohorts, and mechanistic studies before clinical or causal conclusions are drawn.

Humans↗

PubMed2002

Risk estimation for breast cancer development; a clinical perspective.

Breast cancer is the commonest cancer among women and the second highest cause of cancer death. It remains a significant health problem and represents a significant worry for many women and their physician. During the last years, intensive research has been focused on accurate risk estimation for breast cancer development. The aim of these efforts is to identify the "high-risk" group of women for breast cancer development. Preventive strategies (including intensive surveillance, chemoprevention, or prophylactic mastectomy) may be applied for the women at high risk for breast cancer development. Given the many management options, it seems reasonable that management of the high-risk woman be tailored to the level of risk she is willing to accept. In estimating the risk for breast cancer development, several factors should be taken into account (including age, reproductive factors, such as age at menarche and age at menopause or pregnancy and age at first live birth, history of benign breast lesions or breast cancer in situ [LCIS/DCIS], prior history of breast cancer, history of familiar or hereditary breast cancer, and environmental and lifestyle factors). Recently, quantitative risk estimation is possible by combining multiple risk factors into a comprehensible risk expression; this is of significant clinical importance, since it will reduce the considerable variation in management among health care providers. The Gail and the Claus model are the most widely used models for quantitative risk estimation. However, the clinician should understand that all models have some limitations that should be recalled as they are applied. It should be emphasized that risk assessment is a serious undertaking and should only be performed by those who have in-depth knowledge about risk factors, family pedigree analysis, comparative statistics, genetics susceptibility testing and the science of probability.

Anticarcinogenic Agents↗

PubMed1983

The selective utilization of prenatal genetic diagnosis. Experiences of a regional program in upstate New York during the 1970s.

The regional prenatal diagnosis program of the Finger Lakes Health Systems Area in upstate New York has been monitored since its start in 1971. By the end of 1980, more than 1,250 diagnostic procedures had been successfully completed. Based on analyses of regional vital statistics, genetic services data, repeated surveys of obstetricians, and an ongoing survey of recent mothers older than 34 years of age, the authors concluded that: 1) in the study region, most women with an indication for prenatal diagnosis because of age are aware of the possibility of prenatal diagnosis; 2) the majority of obstetricians discuss amniocentesis with their patients; 3) after a period of rapid growth the utilization rate in the study region reached about 40% in 1981; 4) nonuse of prenatal diagnosis is based mostly on a patient's decision rather than system deficiencies; and 5) a community approach to increase utilization will have to focus on how to provide a supportive social climate for these services rather than on increasing awareness among potential patients or more referrals by providers.

Abortion, Induced↗

PubMed1997

Genetic contribution of the endothelial constitutive nitric oxide synthase gene to plasma nitric oxide levels.

Nitric oxide (NO) has an important physiological role in regulating vascular tone and is also relevant to many pathological processes including hypertension and atherosclerosis. Endothelial constitutive nitric oxide synthase (ecNOS) is the key enzyme in determining basal vascular wall NO production. We used a combination of maximum-likelihood-based statistical genetic methods to explore the contributions of the ecNOS gene and other unmeasured genes to basal NO production measured by its metabolites (NOx: nitrite and nitrate) in 428 members of 108 nuclear families. Our initial quantitative genetic analysis estimated that approximately 30% of the variance in fasting NOx levels is due to genes (chi 2(1) = 16.04, P = .000062). Complex segregation analysis detected the effects of both a single locus and residual polygenes on NOx levels, and measured genotype analysis showed that plasma NOx levels in those homozygous for the rare allele (64.9 +/- 7.8 mumol/L) were significantly higher (P = .000242) than those homozygous for the common allele (30.2 +/- 3.1 mumol/L). The results of the variance component linkage analysis were consistent with linkage of a quantitative trait locus in or near the ecNOS gene to variation in plasma NOx levels (P = .0066). While many environmental factors have been shown to alter transiently plasma NOx levels, our study is the first to identify a substantial effect of the ecNOS locus on the variance of plasma NOx, i.e. basal NO production. This finding may be relevant to atherogenesis and NO-related disorders.

Adolescent↗

PubMed2004

[Pedigree analysis and sequence analysis of mtDNA 12srRNA, tRNA(Leu(UUR)), tRNA(Ser(UCN)) gene in nonsyndromic inherited deafness pedigrees].

OBJECTIVE: To investigate the proportion of mtDNA mutation in the non-syndromic genetic hearing loss (NSHL) pedigrees and the genetics statistical formulae for maternal inheritance, to study the relationship of mtDNA mutation and inherited deafness, to identify the incidence of the mtDNA mutation in such pedigrees and sporadic patients with Sensorineural hearing loss (SNHL). METHOD: Twenty-nine pedigrees with NSHL were collected. Pedigree Investigation was taken. Modal Genetics Analysis. Segregation Analysis were taken. Blood samples were obtained from these pedigrees. DNA was extracted from the isolated leukocytes. The mtDNA 1555G, 7445G, 3243G mutation were examined by multiplex PCR. The sequence of 12SrRNA, tRNA(Leu(UUR)) and tRNA(Ser(UCN)) gene were examined. RESULT: There are 12 pedigrees with mtDNA mutation (i.e. 10 with 1555G and 2 with 7445G) examing by multiplex PCR. Modal Genetics Analysis showed that in irregular dominate genetic pedigrees, the incidence of mtDNA mutation is higher than that of regular dominate pedigrees. Segregation Analysis with Screening for mtDNA mutation showed that maternal inherited pedigrees did not have the segregate ratio that the autosomal inheritance had. Sequence analysis confirmed that the 12 pedigrees carried mtDNA mutation, among them 10 pedigrees with 1555G mutation, 2 pedigrees with 7445G mutation, no pedigrees with 3243G. CONCLUSION: Maternal inherited pedigrees do not have the segregate ratio of the autosomal inheritance, mtDNA mutation have high incidence in NSHL, mostly are 1555G and 7445G mutation. Screening for mtDNA 7445G mutation combined with 1555G examination is of value to clinical use. Multiplex PCR can diagnose mtDNA multi-mutation quickly and facilely.

DNA, Mitochondrial↗

PubMed2001

Genetic diversity within and among Pinus pinaster populations: comparison between AFLP and microsatellite markers.

Twenty-three populations of Pinus pinaster (13 Aquitaine populations and 10 Corsican populations) were analysed at three microsatellite loci and 122 AFLP loci. The aims of the study were: (i) to compare levels of within-population and among-population diversity assessed with both kinds of markers; (ii) to compare Aquitaine and Corsican provenances of P. pinaster; and (iii) to know if both markers gave the same information for conservation purposes. Classical population genetics statistics were estimated and the ranking of populations obtained using different markers and/or parameters were compared by computing Spearman's rank correlations. Even though microsatellites showed a higher within-population diversity, they showed the same level of differentiation as AFLP markers. Moreover, both markers also showed a higher genetic diversity in the Aquitaine provenance and a higher differentiation among Corsican populations. AFLPs and microsatellites gave different population diversity rankings. Consequently, the results do not support the potential population identification within each provenance for conservation purposes.

Alleles↗

PubMed1978

Research designs for the study of gene-environment interactions in psychiatric disorders. Report of a Foundations Fund for Research in Psychiatry Panel.

Understanding the genetic and environmental contributions (and their interactions, which are likely to be complex) to the etiology of psychiatric disorders requires research designs incorporating many basic principles of genetics. Genetic variation is likely to contribute to psychiatric disorders and genetic heterogeneity is likely to exist for any single disorder, ie, completely different genetic variants may each be capable of increasing an individual's susceptibility to the disorder. Thus, it is important to define phenotypes that may more closely reflect each individual genetic variant rather than to rely solely on the psychiatric diagnosis. Research should be undertaken with the goal of testing specific hypotheses that can be excluded. Research designs can include studies of unrelated individuals, twins, separated relatives, nuclear families, or extended pedigrees. Not all hypotheses can be tested on one type of data, and appropriate analytic methods vary. Because genetic hypotheses cannot be tested on studies of unrelated individuals, it is important that data be collected on families instead of unrelated individual patients and/or controls. Studies should include traits that bridge the gap between the genotype and the diagnostic phenotype. Such studies should be multidisciplinary, and the best statistical-genetics methodology should be used for data analysis.

Adoption↗

PubMed2000

Cancer control research 2001.

OBJECTIVES: Major societal changes, including the changing demographics of US society and the genetics and communications revolutions, are providing new opportunities to control cancer both in the United States and around the world. This article examines the implications of these trends and other issues in the context of cancer control research. A seven-item strategy for cancer control research is proposed. RESULTS: Epidemiology, statistics, genetics, and bio-behavioral research are central disciplines for cancer control research. The identification of particular at-risk populations is increasingly possible. Cancer control research must focus on increasing fundamental knowledge in order to accelerate improvements in cancer prevention and early detection. Cancer control research also must be used to conduct trials of new cancer detection methods, overcome differential participation in cancer screening, develop evidence-based strategies to improve decision-making, and develop evidence-based cancer communications. A comprehensive cancer surveillance system is the foundation for cancer control research. Cancer control research must aim to reduce cancer risk, incidence, and mortality, and improve quality of life. These are important challenges for the new millennium.

Global Health↗

PubMed1999

Dispersal, gene flow, and population structure.

The accuracy of gene flow estimates is unknown in most natural populations because direct estimates of dispersal are often not possible. These estimates can be highly imprecise or even biased because population genetic structure reflects more than a simple balance between genetic drift and gene flow. Most of the models used to estimate gene flow also assume very simple patterns of movement. As a result, multiple interpretations of population structure involving contemporary gene flow, departures from equilibrium, and other factors are almost always possible. One way to isolate the relative contribution of gene flow to population genetic differentiation is to utilize comparative methods. Population genetic statistics such as FST, heterozygosity and Nei's D can be compared between species with differing dispersal abilities if these species are otherwise phylogenetically, geographically and demographically comparable. Accordingly, the available literature was searched for all groups that meet these criteria to determine whether broad conclusions regarding the relationships between dispersal, population genetic structure, and gene flow estimates are possible. Allozyme and mtDNA data were summarized for 27 animal groups in which dispersal differences can be characterized. In total, genetic data were obtained for 333 species of vertebrates and invertebrates from terrestrial, freshwater and marine habitats. Across these groups, dispersal ability was consistently related to population structure, with a mean rank correlation of -0.72 between ranked dispersal ability and FST. Gene flow estimates derived from private alleles were also correlated with dispersal ability, but were less widely available. Direct-count heterozygosity and average values of Nei's D showed moderate degrees of correlation with dispersal ability. Thus, despite regional, taxonomic and methodological differences among the groups of species surveyed, available data demonstrate that dispersal makes a measurable contribution to population genetic differentiation in the majority of animal species in nature, and that gene flow estimates are rarely so overwhelmed by population history, departures from equilibrium, or other microevolutionary forces as to be uninformative.

Animals↗

PubMed2004

Genetic research in osteoporosis: Where are we? Where should we go next?

Fractures resulting from low bone mass and excessive skeletal fragility (osteoporosis) are common worldwide both in males and females, particularly in later years of life. Both fractures, and the most important predictor of fractures, bone mass, are now known to be strongly heritable. This fact, plus the current growth in genetic science, has led to a surge of genetic research in osteoporosis, mostly in the search for genes and their polymorphisms that are responsible for variation in bone mass. Finding the genetic basis underlying variation in bone mass will lead us to deeper understanding of the biology of bone mass accumulation, maintenance and adaptation to load. This, plus finding the genetic basis for overall variation in fracture risk per se, will facilitate the development of interventions, both pharmaceutical and non-pharmaceutical, to prevent and/or treat osteoporosis successfully. This research has produced a rather large number of gene loci that seem to influence bone mass. The challenge now is to refine the statistical genetics and the phenotypes involved so that we can confidently identify those gene loci that truly influence bone mass, and to find ways to study the genetic basis for the most direct disease outcome of interest, fracture.

Bone Density↗

PubMed2006

Comparative analysis of haplotype association mapping algorithms.

BACKGROUND: Finding the genetic causes of quantitative traits is a complex and difficult task. Classical methods for mapping quantitative trail loci (QTL) in miceuse an F2 cross between two strains with substantially different phenotype and an interval mapping method to compute confidence intervals at each position in the genome. This process requires significant resources for breeding and genotyping, and the data generated are usually only applicable to one phenotype of interest. Recently, we reported the application of a haplotype association mapping method which utilizes dense genotyping data across a diverse panel of inbred mouse strains and a marker association algorithm that is independent of any specific phenotype. As the availability of genotyping data grows in size and density, analysis of these haplotype association mapping methods should be of increasing value to the statistical genetics community. RESULTS: We describe a detailed comparative analysis of variations on our marker association method. In particular, we describe the use of inferred haplotypes from adjacent SNPs, parametric and nonparametric statistics, and control of multiple testing error. These results show that nonparametric methods are slightly better in the test cases we study, although the choice of test statistic may often be dependent on the specific phenotype and haplotype structure being studied. The use of multi-SNP windows to infer local haplotype structure is critical to the use of a diverse panel of inbred strains for QTL mapping. Finally, because the marginal effect of any single gene in a complex disease is often relatively small, these methods require the use of sensitive methods for controlling family-wise error. We also report our initial application of this method to phenotypes cataloged in the Mouse Phenome Database. CONCLUSION: The use of inbred strains of mice for QTL mapping has many advantages over traditional methods. However, there are also limitations in comparison to the traditional linkage analysis from F2 and RI lines. Application of these methods requires careful consideration of algorithmic choices based on both theoretical and practical factors. Our findings suggest general guidelines, though a complete evaluation of these methods can only be performed as more genetic data in complex diseases becomes available.

Algorithms↗

PubMed1994

Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders.

This report employs a statistical genetic approach to analyze quantitative oxygen transport variables in a high-altitude (4,850-5,450 m) native Tibetan population and demonstrates the presence of a major gene influencing % O2 saturation of arterial hemoglobin. This result suggests the hypothesis that individuals with the dominant allele for higher % O2 saturation have a selective advantage at high altitude. Studies of the biologically distinctive Himalayan and Andean populations have greatly influenced thinking about ongoing human evolution and adaptation; this is the first statistical evidence for a major gene enhancing oxygen transport in a high-altitude native population.

Adaptation, Physiological↗

PubMed2006

Genetic and environmental determinants of variation of soluble adhesion molecules.

In our research we examined the contribution of putative genetic sources on interindividual variation and cross-sectional correlations of several adhesion molecules, including intracellular (ICAM-1) and vascular cell adhesion molecules (VCAM-1) and E-selectin, in a population-based sample of ethnically homogeneous families of European origin. The plasma levels of these molecules were measured in 947 apparently healthy individuals from 217 nuclear families. Quantitative statistical-genetic analysis implementing the model fitting technique revealed significant parent/offspring and sibling correlations (p < 0.01) for all three molecules. The putative genetic effects explained 55.2 +/- 7.2% (VCAM-1), 63.3 +/- 7.5% (ICAM) and 63.8 +/- 8.1% (E-selectin) of the variation. Common family environmental factors also significantly influenced the variation of E-selectin (13%) and VCAM-1 (28.6%). The main results of our bivariate analysis showed that the observed phenotypic correlations between ICAM-1 and VCAM-1, and between ICAM-1 and E-selectin, were mostly attributable to shared environmental factors (r(E)= 0.896 and 0.737, respectively; p < 0.01). However, the correlation between VCAM-1 and E-selectin was likely caused by common genetic effects (r(G)= 0.334, p < 0.05). Our results show that familial clustering of adhesion molecules is likely due to strong genetic effects, supplemented with shared environmental factors.

Adolescent↗