A flexible likelihood framework for detecting associations with secondary phenotypes in genetic studies using selected samples: application to sequence data

For most complex trait association studies using next-generation sequencing, in addition to the primary phenotype of interest, many clinically important secondary traits are also available, which can be analyzed to map susceptibility genes. Owing to high sequencing costs, most studies use selected samples, and the sampling mechanisms of these studies can be complicated. When the primary and secondary traits are correlated, analyses of secondary phenotypes can cause spurious associations in selected samples and existing methods are inadequate to adjust for them. To address this problem, a likelihood-based method, MULTI-TRAIT-ASSOCIATION (MTA) was developed. MTA is flexible and can be applied to any study with known sampling mechanisms. It also allows efficient inferences of genetic parameters. To investigate the power of MTA and different study designs, extensive simulations were performed under rigorous population genetic and phenotypic models. It is demonstrated that there are great benefits for analyzing secondary phenotypes in selected samples. In particular, using case-control samples and samples with extreme primary phenotypes can be more powerful than analyzing random samples of equivalent size. One major challenge for sequence-based association studies is that most data sets are not of sufficient size to be adequately powered. By applying MTA, data sets ascertained under distinct mechanisms or targeted at different primary traits can be jointly analyzed to map common phenotypes and greatly increase power. The combined analysis can be performed using freely available data sets from public repositories, for example, dbGaP. In conclusion, MTA will have an important role in dissecting the etiology of complex traits.     

The genetic basis of panic and phobic anxiety disorders

Panic disorder and phobic anxiety disorders are common disorders that are often chronic and disabling. Genetic epidemiologic studies have documented that these disorders are familial and moderately heritable. Linkage studies have implicated several chromosomal regions that may harbor susceptibility genes; however, candidate gene association studies have not established a role for any specific loci to date. Increasing evidence from family and genetic studies suggests that genes underlying these disorders overlap and transcend diagnostic boundaries. Heritable forms of anxious temperament, anxiety-related personality traits and neuroimaging assays of fear circuitry may represent intermediate phenotypes that predispose to panic and phobic disorders. The identification of specific susceptibility variants will likely require much larger sample sizes and the integration of insights from genetic analyses of animal models and intermediate phenotypes.     

The genetic basis of panic disorder

Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.     

DNA Evidence for Strong Genome-Wide Pleiotropy of Cognitive and Learning Abilities

Very different neurocognitive processes appear to be involved in cognitive abilities such as verbal and non-verbal ability as compared to learning abilities taught in schools such as reading and mathematics. However, twin studies that compare similarity for monozygotic and dizygotic twins suggest that the same genes are largely responsible for genetic influence on these diverse aspects of cognitive function. It is now possible to test this evidence for strong pleiotropy using DNA alone from samples of unrelated individuals. Here we used this new method with 1.7 million DNA markers for a sample of 2,500 unrelated children at age 12 to investigate for the first time the extent of pleiotropy between general cognitive ability (aka intelligence) and learning abilities (reading, mathematics and language skills). We also compared these DNA results to results from twin analyses using the same sample and measures. The DNA-based method revealed strong genome-wide pleiotropy: Genetic correlations were greater than 0.70 between general cognitive ability and language, reading, and mathematics, results that were highly similar to twin study estimates of genetic correlations. These results indicate that genes related to diverse neurocognitive processes have general rather than specific effects.     

Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma

Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma- associated phenotypes, we conducted a genome-wide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genome-wide screen has been completed using 292 autosomal and three X-Y pseudoautosomal markers. Using the semi-parametric likelihood ratio chi2 test and the transmission-disequilibrium test, we identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P < 0.01). Markers in four regions (5q23-31, 12q15-24.1, 19q13 and 21q21) showed possible linkage in both the primary and replication samples and have also shown linkage to asthma phenotypes in other samples; two adjacent markers in one additional region (3p24.2-22) showing possible linkage is reported for the first time in the Hutterites. The results suggest that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population.      

Gene set analysis of SNP data: benefits, challenges, and future directions

The last decade of human genetic research witnessed the completion of hundreds of genome-wide association studies (GWASs). However, the genetic variants discovered through these efforts account for only a small proportion of the heritability of complex traits. One explanation for the missing heritability is that the common analysis approach, assessing the effect of each single-nucleotide polymorphism (SNP) individually, is not well suited to the detection of small effects of multiple SNPs. Gene set analysis (GSA) is one of several approaches that may contribute to the discovery of additional genetic risk factors for complex traits. Complex phenotypes are thought to be controlled by networks of interacting biochemical and physiological pathways influenced by the products of sets of genes. By assessing the overall evidence of association of a phenotype with all measured variation in a set of genes, GSA may identify functionally relevant sets of genes corresponding to relevant biomolecular pathways, which will enable more focused studies of genetic risk factors. This approach may thus contribute to the discovery of genetic variants responsible for some of the missing heritability. With the increased use of these approaches for the secondary analysis of data from GWAS, it is important to understand the different GSA methods and their strengths and weaknesses, and consider challenges inherent in these types of analyses. This paper provides an overview of GSA, highlighting the key challenges, potential solutions, and directions for ongoing research.     

Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits

Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P?相似文献   

Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.Subject terms: Genetic variation, Genome-wide association studies     

Twins for epigenetic studies of human aging and development

Most of the complex traits including aging phenotypes are caused by the interaction between genome and environmental conditions and the interface of epigenetics may be a central mechanism. Although modern technologies allow us high-throughput profiling of epigenetic patterns already at genome level, our understanding of genetic and environmental influences on the epigenetic processes remains limited. Twins are of special interest for genetic studies due to their genetic similarity and rearing-environment sharing. The classical twin design has made a great contribution in dissecting the genetic and environmental contributions to human diseases and complex traits. In the era of functional genomics, the valuable sample of twins is helping to bridge the gap between gene activity and the environments through epigenetic mechanisms unlimited by DNA sequence variations. We propose to extend the classical twin design to study the aging-related molecular epigenetic phenotypes and link them with environmental exposures especially early life events. Different study designs and application issues will be highlighted and novel approaches introduced with aim at making uses of twins in assessing the environmental impact on epigenetic changes during development and in the aging process.     

Neural phenotypes of common and rare genetic variants

Neuroimaging methods offer a powerful way to bridge the gaps between genes, neurobiology and behavior. Such investigations may be further empowered by complementary strategies involving chromosomal abnormalities associated with particular neurobehavioral phenotypes, which can help to localize causative genes and better understand the genetics of complex traits in the general population. Here we review the evidence from studies using these convergent approaches to investigate genetic influences on brain structure: (1) studies of common genetic variations associated with particular neuroanatomic phenotypes, and (2) studies of possible 'genetic subtypes' of neuropsychiatric disorders with very high penetrance, with a focus on neuroimaging studies using novel computational brain mapping algorithms. Finally, we discuss the contribution of behavioral neurogenetics research to our understanding of the genetic basis of neuropsychiatric disorders in the broader population.     

Appropriate Use of Information on Family History of Disease in Recruitment for Linkage Analysis Studies

When conducting genetic studies for complex traits, large samples are commonly required to detect any of the number of genes with relatively low effect thought to underly such traits. This is because, in contrast to monogenic diseases, complex traits typically result from a number of different genetic pathways (genetic heterogeneity) and any sample is likely to contain a considerable fraction of sporadic cases (phenocopies). Such samples are time-consuming and costly to recruit and analyse. Methods which might be used to decrease sample size include attempting to select families, with the aim of reducing genetic heterogeneity or phenocopy rate within the sample. Selecting cases with positive family history of disease should reduce the phenocopy rate, and this strategy has been employed in linkage studies of complex disease, although evaluations of such a strategy have been equivocal.
This paper shows how identity by descent (IBD) distributions may be calculated for affected relative pairs recruited conditional on the affection status of a third relative. These distributions are then used to calculate expected power in affected sib and half-sib linkage studies when recruitment is conditional on family history of disease. We consider the proxy conditions of recruitment conditional on disease in an affected parent or third sibling with single-locus and additive multilocus genetic models. We show that while such selection strategies can reduce power if disease risk alleles are common and environmental heterogeneity low, under models more likely to underly common complex diseases power will generally be increased, and that this effect is greater as more loci are involved. Though the proxy cases studied are more extreme than a general strategy of asking potential recruits whether they have any family history of disease, these results suggest that conditional recruitment is more generally useful than previous studies have suggested.     

Preface and Overview: Genetics of SLE; A sine qua non for identification

Clinical manifestations of systemic lupus erythematosus (SLE) are extremely diverse and variable, mainly because SLE is a multi-factorial disease. Variable combinations of contributing genes at multiple loci in individual patients probably result in diverse disease phenotypes. Genes that predispose to SLE are undoubtedly related to key events in pathogenesis, and may involve a variety of genes in immune system. These genes are currently unidentified, mostly because of the complexity of multi-factorial inheritance. Recently, the application of the polymerase chain reaction and the availability of maps of microsatellites have facilitated a genome-wide scan to define the number and locations of genes for complex traits. However, extensive genetic heterogeneities and polymorphisms and complex modes of inheritance of disease phenotypes have delayed completion of a genome-wide analysis of susceptibility loci for human SLE. Since many SLE-susceptibility genes show low penetrance, several hundred affected sibpairs are assumed to be necessary to show linkages for many of the contributing loci. In this respect, studies of polymorphisms and functions of candidate genes suggested based on studies on murine models may contribute to studies on SLE patients and their relatives. Major genetic loci have been mostly identified in SLE-prone mouse strains. Nevertheless, identity of natures, functions and roles in the pathogenesis of SLE remains undetermined. Considering the possibility of clustering of susceptibility loci in a particular chromosomal interval, the final goal for identification of susceptibility genes will largely depend on the generation of mutant SLE-prone mice with homologous recombination of the potential target gene. Extensive reviews collected here are expected to form the basis for identification of target genes and for clarification of the genetic mechanisms underlying SLE.     

Preface and overview: genetics of SLE; a sine qua non for identification

Clinical manifestations of systemic lupus erythematosus (SLE) are extremely diverse and variable, mainly because SLE is a multi-factorial disease. Variable combinations of contributing genes at multiple loci in individual patients probably result in diverse disease phenotypes. Genes that predispose to SLE are undoubtedly related to key events in pathogenesis, and may involve a variety of genes in immune system. These genes are currently unidentified, mostly because of the complexity of multi-factorial inheritance. Recently, the application of the polymerase chain reaction and the availability of maps of microsatellites have facilitated a genome-wide scan to define the number and locations of genes for complex traits. However, extensive genetic heterogeneities and polymorphisms and complex modes of inheritance of disease phenotypes have delayed completion of a genome-wide analysis of susceptibility loci for human SLE. Since many SLE-susceptibility genes show low penetrance, several hundred affected sibpairs are assumed to be necessary to show linkages for many of the contributing loci. In this respect, studies of polymorphisms and functions of candidate genes suggested based on studies on murine models may contribute to studies on SLE patients and their relatives. Major genetic loci have been mostly identified in SLE-prone mouse strains. Nevertheless, identity of natures, functions and roles in the pathogenesis of SLE remains undetermined. Considering the possibility of clustering of susceptibility loci in a particular chromosomal interval, the final goal for identification of susceptibility genes will largely depend on the generation of mutant SLE-prone mice with homologous recombination of the potential target gene. Extensive reviews collected here are expected to form the basis for identification of target genes and for clarification of the genetic mechanisms underlying SLE.     

Genetics of human brain oscillations.

In the last three decades, much emphasis has been placed on neural oscillations in vitro, in vivo, as well as in the human brain. These brain oscillations have been studied extensively in the resting electroencephalogram (EEG), as well as in the underlying evoked oscillations that make up the event-related potentials (ERPs). There are several approaches to elucidate the possible mechanisms of these brain oscillations. One approach is to look at the neurophysiology and neurochemistry involved in generating and modulating these oscillations. Another more recent approach is to examine the genetic underpinnings of these neural oscillations. It is proposed that the genetic underpinnings of these oscillations are likely to stem from regulatory genes which control the neurochemical processes of the brain, and therefore influence neural function. Genetic analyses of human brain oscillations may identify genetic loci underlying the functional organization of human neuroelectric activity. Brain oscillations represent important correlates of human information processing and cognition. They represent highly heritable traits that are less complex and more proximal to gene function than either diagnostic labels or traditional cognitive measures. Therefore these oscillations may be utilized as phenotypes of cognition and as valuable tools for the understanding of some complex genetic disorders. Genetic loci that have been recently identified regarding both resting and evoked brain oscillations involving the GABAergic and cholinergic neurotransmitter systems of the brain are discussed. It is concluded that the advent of genomics and proteomics and a fuller understanding of gene regulation will open new horizons on the critical electrical events so essential for human brain function.     

The value of isolated populations in genetic studies of allergic diseases

Asthma and other IgE-mediated atopic disorders are extremely common in the population, with a consistent, but rather small, genetic component (lambda 3-5) in the inheritance of the disease. So far, genome-wide gene mapping studies in asthma-related traits have not achieved the same success as the positional cloning of genes for Mendelian diseases. Many disease predisposing alleles are believed to be involved in the development of these phenotypes, but at present we do not understand their genetic architecture. As a result of reduced allelic diversity and longer-range linkage disequilibrium compared with more mixed populations, isolated populations may offer a unique opportunity to model a simplified picture of these complex genetic events predisposing to common diseases, such as asthma, which demonstrate familial clustering, but do not follow a simple Mendelian mode of inheritance.(sib)     

Genetic Covariation Underlying Reading,Language and Related Measures in a Sample Selected for Specific Language Impairment

Specific language impairment is a developmental language disorder characterized by failure to develop language normally in the absence of a specific cause. Previous twin studies have documented the heritability of reading and language measures as well as the genetic correlation between those measures. This paper presents results from an alternative to the classical twin designs by estimating heritability from extended pedigrees. These pedigrees were previously studied as part of series of molecular genetic studies of specific language impairment where the strongest genetic findings were with reading phenotypes rather than language despite selecting pedigrees based on language impairments. To explore the relationship between reading and language in these pedigrees, variance components estimates of heritability of reading and language measures were conducted showing general agreement with the twin literature, as were genetics correlations between reading and language. Phonological short-term memory, phonological awareness and auditory processing were evaluated as candidate mediators of the reading-language genetic correlations. Only phonological awareness showed significant genetic correlations with all reading measures and several language measures while phonological short-term memory and auditory processing did not.     

Life is pain: Fibromyalgia as a nexus of multiple liability distributions

Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare-based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co-occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital-associated biobank data, falling into three broad categories of pain-related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome-wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome-wide association analysis of fibromyalgia in biobank samples, which did not result in any genome-wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.     

The success of the genome-wide association approach: a brief story of a long struggle

The genome-wide association approach has been the most powerful and efficient study design thus far in identifying genetic variants that are associated with complex human diseases. This approach became feasible as the result of several key advancements in genetic knowledge, genotyping technologies, statistical analysis algorithms and the availability of large collections of cases and controls. With all these necessary tools in hand, many genome-wide association studies were recently completed, and many more studies which will explore the genetic basis of various complex diseases and quantitative traits are soon to come. This approach has started to reap the fruits of its labor over the past several months. Publications of genome-wide association studies in several complex diseases such as inflammatory bowel disease, type-2 diabetes, breast cancer and prostate cancer have been abundant in the first half of this year. The aims of this review are firstly, to provide a timely summary for most of the genome-wide association studies that have been published until June/July 2007 and secondly, to evaluate to what extent these results have been validated in subsequent replication studies.     

Genetic selection for resistance or susceptibility to oral tolerance imparts correlation to both Immunoglobulin E level and mast cell number phenotypes with a profound impact on the atopic potential of the individual

Background Immunological oral tolerance is being studied with great interest due to its therapeutic potential in allergy and autoimmunity processes, although the cellular and molecular mechanisms linking these different phenomena remain elusive. In the present study, two mouse lines with extreme phenotypes for susceptibility [TS Line] or resistance [TR Line] to oral tolerance and their [TS × TR]F₂ segregants were used in order to evaluate the impact of these traits on the atopic potential of the individuals. Objective Demonstrate whether the tr and ts genes, cumulated during 18 generations of bidirectional genetic selection, influence expression of two important immunobiological traits (IgE and mast cell) critical to allergic response. Methods Mice with extreme phenotypes for oral tolerance to ovalbumin (OVA), produced by assortative mating (TS and TR Line), and their (TS × TR)F₂ segregating were used. Serum IgE levels assayed by ELISA, and mastocytes counted with toluidine blue staining were evaluated in naïve mice. Anaphylaxis was induced by intravenous injection of OVA, intestinal inflammation by oral administration of OVA 7 days after immunization, and pulmonary inflammation by intranasal and nebulization OVA challenges. Specific IgE was dosed by passive cutaneous anaphylaxis. Results The naïve TS mice have a 20‐fold lower serum IgE level and two‐ to threefold diminished mast cell numbers in mucosal sites, when compared with TR‐mice, which were highly susceptible to allergic inflammation and anaphylactic shock. The associations of oral tolerance, serum IgE levels and mast cell numbers in naïve animals were confirmed analysing the simultaneous presence of these traits in individuals of a [TS × TR]F₂‐segregating population. Conclusion The results suggest that the complex of genes controlling TS and TR phenotypes play a main role in the regulation of the atopic potential of the individual. The studies of these traits in interline F₂ segregants demonstrated a co‐segregation of TS and TR phenotypes with IgE responsiveness and mast cell numbers. Thus, the opposite capacity of the genetically modified mice may be involved in co‐adaptative mechanisms reflecting a dynamic relation between gene frequencies in a natural population. These correlations give circumstantial evidence to support clinical applications of oral tolerance in allergic and autoimmune diseases.     

Genetic approaches to stature, pubertal timing, and other complex traits

The factors that regulate the timing of puberty remain largely elusive, as do the factors that modulate childhood growth and adult height. However, it is clear that these developmental processes are highly heritable--much of the natural variation in growth and timing of puberty is due to genetic variation within the population. In this review, we discuss how recent genetic and genomic advances can be exploited to help understand the genetic regulation of these processes. In particular, we describe how genome-wide linkage scans and association studies, in conjunction with haplotype-based approaches, are potentially useful tools to increase our understanding of these two complex traits. Discovery of the genetic variants that regulate these two traits would expand our understanding of human neuroendocrinology, postnatal development, and the general architecture of complex genetic traits.