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PubMed1999

Quantitative genetics in conservation biology.

Most of the major genetic concerns in conservation biology, including inbreeding depression, loss of evolutionary potential, genetic adaptation to captivity and outbreeding depression, involve quantitative genetics. Small population size leads to inbreeding and loss of genetic diversity and so increases extinction risk. Captive populations of endangered species are managed to maximize the retention of genetic diversity by minimizing kinship, with subsidiary efforts to minimize inbreeding. There is growing evidence that genetic adaptation to captivity is a major issue in the genetic management of captive populations of endangered species as it reduces reproductive fitness when captive populations are reintroduced into the wild. This problem is not currently addressed, but it can be alleviated by deliberately fragmenting captive populations, with occasional exchange of immigrants to avoid excessive inbreeding. The extent and importance of outbreeding depression is a matter of controversy. Currently, an extremely cautious approach is taken to mixing populations. However, this cannot continue if fragmented populations are to be adequately managed to minimize extinctions. Most genetic management recommendations for endangered species arise directly, or indirectly, from quantitative genetic considerations.

Animals↗
PubMed1999

Clines in polygenic traits.

This article outlines theoretical models of clines in additive polygenic traits, which are maintained by stabilizing selection towards a spatially varying optimum. Clines in the trait mean can be accurately predicted, given knowledge of the genetic variance. However, predicting the variance is difficult, because it depends on genetic details. Changes in genetic variance arise from changes in allele frequency, and in linkage disequilibria. Allele frequency changes dominate when selection is weak relative to recombination, and when there are a moderate number of loci. With a continuum of alleles, gene flow inflates the genetic variance in the same way as a source of mutations of small effect. The variance can be approximated by assuming a Gaussian distribution of allelic effects; with a sufficiently steep cline, this is accurate even when mutation and selection alone are better described by the 'House of Cards' approximation. With just two alleles at each locus, the phenotype changes in a similar way: the mean remains close to the optimum, while the variance changes more slowly, and over a wider region. However, there may be substantial cryptic divergence at the underlying loci. With strong selection and many loci, linkage disequilibria are the main cause of changes in genetic variance. Even for strong selection, the infinitesimal model can be closely approximated by assuming a Gaussian distribution of breeding values. Linkage disequilibria can generate a substantial increase in genetic variance, which is concentrated at sharp gradients in trait means.

Alleles↗
PubMed1999

Estimating genetic correlations in natural populations.

Information on the genetic correlation between traits provides fundamental insight into the constraints on the evolutionary process. Estimates of such correlations are conventionally obtained by raising individuals of known relatedness in artificial environments. However, many species are not readily amenable to controlled breeding programmes, and considerable uncertainty exists over the extent to which estimates derived under benign laboratory conditions reflect the properties of populations in natural settings. Here, non-invasive methods that allow the estimation of genetic correlations from phenotypic measurements derived from individuals of unknown relatedness are introduced. Like the conventional approach, these methods demand large sample sizes in order to yield reasonably precise estimates, and special precautions need to be taken to eliminate bias from shared environmental effects. Provided the sample consists of at least 20% or so relatives, informative estimates of the genetic correlation are obtainable with sample sizes of several hundred individuals, particularly if supplemental information on relatedness is available from polymorphic molecular markers.

Animals↗
PubMed2026

Polygenic risk factors for comorbid diagnoses in individuals with substance use disorders: A phenome-wide survival analysis.

OBJECTIVE: Persons with substance use disorders (SUD) often suffer from additional comorbidities. Researchers have explored this overlap via phenome-wide association studies (PheWASs). However, PheWASs are largely cross-sectional, limiting our understanding of whether diagnoses predate the development of an SUD. We characterize whether polygenic scores (PGSs) are associated with time to comorbid diagnoses in electronic health records (EHR) after the first documented SUD diagnosis. METHODS: Using data from All of Us (N&#xa0;=&#xa0;393,596), we explored: (1) whether social determinants of health (SDoHs) are associated with lifetime risk of SUD (N cases&#xa0;=&#xa0;42,568) and (2) within a subset those with a diagnosed SUD and available genetic data SUD (N&#xa0;=&#xa0;21,357), whether PGS for alcohol use disorders, cannabis use disorders, depression, externalizing, posttraumatic stress disorder, and schizophrenia were associated with subsequent diagnoses via a phenome-wide survival analysis. RESULTS: Multiple SDoHs were associated with lifetime SUD diagnosis, with annual household income having the largest overall associations (e.g. <$10&#xa0;K annually vs $100&#xa0;K-$150&#xa0;K annually: OR&#xa0;=&#xa0;4.18; 95% CI&#xa0;=&#xa0;3.92, 4.45). There were 86 phenome-wide significant PGS associations with subsequent diagnoses across various bodily systems. PGSs for alcohol use disorders, posttraumatic stress disorder, and schizophrenia were each associated with time to their respective diagnoses. CONCLUSIONS: Social determinants, especially those related to income, have profound associations with lifetime SUD risk. Additionally, PGSs for psychiatric conditions are associated with multiple post-SUD diagnoses within those with a SUD, suggesting PGS may capture information beyond lifetime risk, including timing and severity of comorbidities related to SUD.

Humans↗
PubMed2026

Unravelling sex differences in the genetic architecture of anxiety.

BACKGROUND: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. METHODS: Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. RESULTS: In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI. CONCLUSIONS: While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.

Female↗
PubMed1998

Etiology of Balkan endemic nephropathy: a multifactorial disease?

Balkan endemic nephropathy (BEN) is of great clinical importance in the restricted areas of Bulgaria, Rumania, Croatia, Serbia, Bosnia and Herzegovina. So far, studies on the etiological factors for BEN have not discovered any single environmental causative agent of this puzzling disease. These data reject the possibility of a purely environmental causation of BEN. The pattern of BEN transmission in the risk families is not typical for single gene disorders. Extensive epidemiological and genetic studies disclose characteristics of multifactorial (polygenic) inheritance of BEN. The evidences of 'familial tendency', variation of the risk for BEN depending on the number of sick parents and the degree of relatedness; the development of BEN in individuals from at-risk families who were born in non-endemic areas; the data that disease is not found in the gypsy population and the expressions of 3q25 cytogenetic marker suggest that the genetic factors play an important role as causative factors in BEN development. The possible impact of environmental triggers on individuals genetically predisposed to BEN could be supposed by the following data: the cytogenetic results of the increased frequency of folate sensitive Fra sites, spontaneous or radiation-induced aberrations in several bands in BEN patients, the data from the detailed analysis of breaks in BEN patients and controls that generate structural chromosome aberrations; the occurrence of BEN in immigrants. Genetical epidemiological approaches to etiology and prevention of BEN are proposed. The predisposing genes for BEN could be genes localized in a region between 3q25-3q26; transforming growth factor-beta (TGF-beta), genetic heterogeneity of xenobiotic-metabolizing enzymes; defects in the host's immune system. The predisposing genes for BEN patients with urinary tract tumors could be germline mutations in tumor suppressor genes and acquired somatic mutations in oncogenes.

Balkan Nephropathy↗
PubMed2002

Including measured genotypes in statistical models to study the interplay of multiple factors affecting complex traits.

The etiology of complex traits may perhaps best be conceptualized by an interplay of multiple factors that mediate the influence of the genes on the eventual outcome. The possibilities of studying aspects of this interplay using existing methods are generally limited. We therefore propose a model with observed and latent variables that does not impose restrictions on the number of variables or the direction of their causal relations and provides a general approach for fitting structural equation models to empirical data. The model is very flexible and (1) allows for genetic effects on the means, variances, and relations between variables, (2) can control for stratification effects on all these components, (3) can be fitted in nuclear families of any size, (4) is estimated using an interpretable parameterization, and (5) can incorporate di- and multi-allelic loci, marker haplotypes, multiple loci simultaneously, and parental genotypes. We indicate how the model can be estimated with the Mx software (Neale et al., 1999) and have written a program to enable geneticists who are not acquainted with Mx to fit their own submodels in a simple and efficient way. A simulation study showed that the model yielded correct Type I errors, unbiased parameter estimates, and satisfactory power to discriminate between alternative models. An example is also given that illustrates how the model could be applied to real data.

Gene Frequency↗
PubMed2004

A simulation study concerning the effect of varying the residual phenotypic correlation on the power of bivariate quantitative trait loci linkage analysis.

The power of bivariate variance components (VC) linkage analysis is affected by the size and source of the phenotypic correlation between variables. In particular, several authors have suggested that the power to detect linkage is greatest when the quantitative trait locus (QTL) and residual sources of variation induce phenotypic covariation in opposite directions, and that this increase in power is greatest when unique environmental sources of variation induce covariation in the direction opposite to the QTL. The purpose of the present study was to investigate further the effect of varying the residual correlation between variables on the power to detect linkage in a bivariate variance components linkage analysis. Data were simulated for a biallelic QTL that pleiotropically influenced two variables. The power to detect linkage was calculated under a variety of situations in which the proportion of phenotypic covariance resulting from shared sources of variation and from unique sources of variation was varied. These simulations were performed for the case in which the QTL affected the two variables equally and also for the case in which the QTL made unequal contributions to each variable. Our results confirm that the power to detect QTLs in a bivariate test for linkage depends upon the size and source of the residual correlation between variables, being greatest when the QTL and unique environmental sources of variation induce phenotypic covariation in opposite directions. We also found that when the QTL affected the two variables unequally, the power to detect linkage increased markedly as the correlation between unique environmental sources of variation increased from 0.6 to 0.9. Similar results were obtained under a variety of genetic models, including when there were unequal allele frequencies and dominance at the QTL. We suggest that a promising strategy to increase the power to detect QTLs might be to collect data from variables where there is either good observational evidence (e.g., from multivariate structural equation modeling of twin data) or a sound theoretical argument that the QTL and environmental factors induce covariation in opposite directions.

Alleles↗
PubMed2000

Genetic polymorphism and clinical outcome: identification of individuals at risk of a poor clinical outcome.

Susceptibility and outcome in complex disorders such as asthma and cancer appear to be determined, at least in part, by genetic polymorphism. However, while our ability to identify new allelic variants and study them in case and control populations has greatly improved, considerable difficulties remain in elucidating how many genes determine particular clinical phenotypes. This is because most studies have concentrated on study of single genes in relatively small study groups. The important issues of gene-gene interactions (epistasis) and high-risk subgroups have not yet been adequately addressed. We now describe a general approach, using patients with head and neck cancers as an example. Our purpose is to demonstrate candidate gene selection, statistical approaches, and identification of patient subgroups.

Genetic Predisposition to Disease↗
PubMed1999

Aicardi-Goutières syndrome: monogenic recessive disease, genetically heterogeneous disease, or multifactorial disease?

Aicardi-Goutières syndrome (AGS) is a severe progressive familial encephalopathy, which is usually diagnosed shortly after birth. Using the principle of homozygosity mapping, genome-wide screening of five consanguineous families was performed to search for a homozygous region shared by all affected individuals. A total of 364 markers with an average spacing of 9.9 cM were genotyped, but no homozygous region common to all affected individuals could be found. Regions of homozygosity in affected sibs could only be identified within each family individually. This may reflect genetic heterogeneity, possibly related to clinical heterogeneity, since several syndromes are clinically difficult to distinguish from AGS. Involvement of a small number of genes and/or of an external factor, such as infection, may also explain the absence of a homozygous region common to all affected individuals.

Abnormalities, Multiple↗
PubMed2000

A multivariate analysis of 59 candidate genes in personality traits: the temperament and character inventory.

Cloninger (Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science 1987: 236: 410-416) proposed three basic personality dimensions for temperament: novelty seeking, harm avoidance, and reward dependence. He suggested that novelty seeking primarily utilized dopamine pathways, harm avoidance utilized serotonin pathways, and reward dependence utilized norepinephrine pathways. Subsequently, one additional temperament dimension (persistence) and three character dimensions (cooperativeness, self-directedness, and self-transcendence) were added to form the temperament and character inventory (TCI). We have utilized a previously described multivariate analysis technique (Comings DE, Gade-Andavolu R, Gonzalez N et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196; Comings DD, Gade-Andavolu R, Gonzalez N et al. Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder. Clin Genet 2000: in press) to examine the relative role of 59 candidate genes in the seven TCI traits and test the hypothesis that specific personality traits were associated with specific genes. While there was some tendency for this to be true, a more important trend was the involvement of different ratios of functionally related groups of genes, and of different genotypes of the same genes, for different traits.

Adult↗
PubMed2003

Sib-pairs in multifactorial disorders: the sib-similarity problem.

Common disorders are, by definition, the major cause of ill health and death. Most can be modified by avoiding or shielding an environment, as in sunburn and coeliac disease, by replacing some deficient substance, as in diabetes or myxoedema, or by empirical methods of evident effect as in schizophrenia and depressive illness. As expected, all show an increased incidence in relatives and the identification of the more influential loci involved may define unexpected links in the metabolic map: these may be amenable to therapy, or, in autoimmune disorders and asthma, define precipitating factors by sequencing the receptor involved. The major investment in trawling the genotype for influential loci has been by affected sib-pairs with parents (ASPs). Over a hundred major studies have been published with very limited success. No substantial study of normal sib-pairs has been undertaken, making this family of surveys one of the largest undertaken in the absence of controls. Possible reasons for this limited success and the many suggestive false positives are considered.

False Positive Reactions↗
PubMed2003

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.

Adolescent↗
PubMed2005

Epistasis and balanced polymorphism influencing complex trait variation.

Complex traits such as human disease, growth rate, or crop yield are polygenic, or determined by the contributions from numerous genes in a quantitative manner. Although progress has been made in identifying major quantitative trait loci (QTL), experimental constraints have limited our knowledge of small-effect QTL, which may be responsible for a large proportion of trait variation. Here, we identified and dissected a one-centimorgan chromosome interval in Arabidopsis thaliana without regard to its effect on growth rate, and examined the signature of historical sequence polymorphism among Arabidopsis accessions. We found that the interval contained two growth rate QTL within 210 kilobases. Both QTL showed epistasis; that is, their phenotypic effects depended on the genetic background. This amount of complexity in such a small area suggests a highly polygenic architecture of quantitative variation, much more than previously documented. One QTL was limited to a single gene. The gene in question displayed a nucleotide signature indicative of balancing selection, and its phenotypic effects are reversed depending on genetic background. If this region typifies many complex trait loci, then non-neutral epistatic polymorphism may be an important contributor to genetic variation in complex traits.

Arabidopsis↗