Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study

Genome-wide association studies (GWAS) have become increasingly popular recently and contributed to the discovery of many susceptibility variants. However, a large proportion of the heritability still remained unexplained. This observation raises queries regarding the ability of GWAS to uncover the genetic basis of complex diseases. In this study, we propose a simple and fast statistical framework to estimate the total heritability explained by all true susceptibility variants in a GWAS. It is expected that many true risk variants will not be detected in a GWAS due to limited power. The proposed framework aims at recovering the "hidden" heritability. Importantly, only the summary z-statistics are required as input and no raw genotype data are needed. The strategy is to recover the true effect sizes from the observed z-statistics. The methodology does not rely on any distributional assumptions of the effect sizes of variants. Both binary and quantitative traits can be handled and covariates may be included. Population-based or family-based designs are allowed as long as the summary statistics are available. Simulations were conducted and showed satisfactory performance of the proposed approach. Application to real data (Crohn's disease, HDL, LDL, and triglycerides) reveals that at least around 10-20% of variance in liability or phenotype can be explained by GWAS panels. This translates to around 10-40% of the total heritability for the studied traits.     

Genetic influences on mannan-binding lectin (MBL) and mannan-binding lectin associated serine protease-2 (MASP-2) activity

The lectin pathway of the complement system is activated when Mannan-binding lectin (MBL) in complex with MASP-2 binds microorganisms. Polymorphisms in both genes are responsible for low serum levels, which associate with increased risk of infection and autoimmune disease. The present study includes 1215 MBL measurements and 1214 MASP-2 activity measurements in healthy Danish adult twins. Total MASP-2 activity was estimated by C4 cleaving activity of samples diluted in an excess of MBL. Twin-twin correlations were higher in monozygotic (MZ) than in dizygotic (DZ) twins for both traits. Heritabilites of MBL levels and MASP-2 activity were estimated using structural equation modeling allowing assessment of the contribution of common genes affecting both traits. The estimated heritability was 0.77 [95% CI 0.64;0.91] for MBL levels and 0.75 [95% CI 0.59;0.81] for MASP-2 activity with the presence of additive genetic factors, shared environmental factors, and non-shared environmental factors. The genetic correlation, i.e., common genetic factors affecting MBL and MASP-2 activity was estimated to r(g) = 0.34 [0.25;0.42]. The data indicate a strong genetic influence for the serum levels of MBL and for MASP-2 activity with a significant genetic correlation between the two traits.     

Path analysis of seven fear factors in adult twin and sibling pairs and their parents

A multivariate path model of genetic and environmental transmission, used to derive expected covariances among adult twin and sibling pairs and their parents, was fitted to fear factor data from 250 twin families and 91 sibling families, with the use of a maximum-likelihood estimation procedure. The full model, with 259 free parameters, provides for parental cultural transmission, common twin and sibling environment, genotype-environment correlation, direct assortative mating, and genetic and environmental correlations. Significant effects were indicated for heritable transmission of common fears and phobias, and a single genetic factor accounted for most of the genetic covariance among the traits. Moderately high levels of common twin environment and a small effect for direct isomorphic marital assortment were also found. There was no evidence for cultural transmission, genotype-environment correlation, or common sibling environment.     

Diet Quality and Risk of Lung Cancer in the Multiethnic Cohort Study

Diet quality, assessed by the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII^®), was examined in relation to risk of lung cancer in the Multiethnic Cohort Study. The analysis included 179,318 African Americans, Native Hawaiians, Japanese Americans, Latinos, and Whites aged 45–75 years, with 5350 incident lung cancer cases during an average follow-up of 17.5 ± 5.4 years. In multivariable Cox models comprehensively adjusted for cigarette smoking, the hazard ratios (95% confidence intervals) for the highest vs. lowest quality group based on quintiles were as follows: 0.85 (0.77–0.93) for HEI-2015; 0.84 (0.77–0.92) for AHEI-2010; 0.83 (0.76–0.91) for aMED; 0.83 (0.73–0.91) for DASH; and 0.90 (0.82–0.99) for DII. In histological cell type-specific analyses, the inverse association was stronger for squamous cell carcinoma than for adeno-, small cell, and large cell carcinomas for all indexes. There was no indication of differences in associations by sex, race/ethnicity, and smoking status. These findings support that high-quality diets are associated with lower risk of lung cancer, especially squamous cell carcinomas, in a multiethnic population.     

Polygenic Epidemiology

Much of the genetic basis of complex traits is present on current genotyping products, but the individual variants that affect the traits have largely not been identified. Several traditional problems in genetic epidemiology have recently been addressed by assuming a polygenic basis for disease and treating it as a single entity. Here I briefly review some of these applications, which collectively may be termed polygenic epidemiology. Methodologies in this area include polygenic scoring, linear mixed models, and linkage disequilibrium scoring. They have been used to establish a polygenic effect, estimate genetic correlation between traits, estimate how many variants affect a trait, stratify cases into subphenotypes, predict individual disease risks, and infer causal effects using Mendelian randomization. Polygenic epidemiology will continue to yield useful applications even while much of the specific variation underlying complex traits remains undiscovered.     

“All Colors and Hues”: An Autoethnography of a Multiethnic Family's Strategies for Bilingualism and Multiculturalism

This two‐year autoethnographic action research study explores the processes a multiethnic/multiracial family uses to maintain their children's heritage language of Spanish and the family's multiculturalism. Data sources (including interviews and participant observations in the home and the dual‐language school) specifically focus on the eldest child, Nelia, from her kindergarten and first‐grade years where she attended a public dual‐language program. The findings illuminate the integral link between the family's ideology toward valuing bilingualism and the necessity of school support.     

Ever vs Never Smoking among an Urban, Multiethnic Sample of Haitian-, Caribbean-, and U.S.-Born Blacks

Background.Despite the high rate of current smoking among blacks in the United States, to date there have been no studies comparing smoking rates or predictors of smoking among adults from different black ethnic groups living in the United States. If cancer control programs are to successfully reduce the risk of smoking-related cancers within black communities, more extensive data on demographics, knowledge, attitudes, beliefs, and practices within ethnic groups are needed.Methods.We conducted a structured telephone interview to assess smoking status, alcohol use, cancer-related attitudes and beliefs, and demographic information among Haitian-born (N= 165), Caribbean-born (N= 354), and U.S.-born (N= 402) blacks living in New York City in 1992.Results.Relative to U.S.-born participants, both Caribbean- and Haitian-born participants were significantly less likely to have ever smoked. Although both groups of foreign-born men were much more likely to have ever smoked relative to their female counterparts, U.S.-born men and women were equally likely to have ever smoked. Alcohol use was consistently related to smoking across ethnic and gender groups, and this association was enhanced among older drinkers. The belief that smoking is not related to cancer was associated with an almost twofold increase of ever smoking.Conclusions.The rate of ever smoking among urban, foreign-born blacks is considerably lower than among U.S.-born blacks; among the foreign-born participants, ever smoking was lower among women relative to men. Alcohol use is an important predictor of smoking status, particularly among older drinkers.     

Parenting,Family Processes,Relationships, and Parental Support in Multiracial and Multiethnic Families: An Exploratory Study of Youth Perceptions

Mixed‐race or multiethnic youth are at risk for mental and physical health problems. We used data from the National Longitudinal Study of Youth 1997 to compare family characteristics of adolescents of a mixed‐race or multiethnic background with those of a monoracial or monoethnic background. Mixed‐race or multiethnic youth reported feeling less supported by parents and reported less satisfactory parent‐adolescent relationships. Mixed‐race/multiethnic youth were more like monoracial White youth in terms of being independent but were more like racial or ethnic minorities (African Americans, Hispanics) in regard to family activities. Reasons for these findings are explored. We discuss the need for future research on the experiences of mixed‐race/multiethnic youth.     

Statistical methodology for estimating twin similarity with respect to a dichotomous trait

Statistical methodology is presented for the estimation of twin similarity with respect to a dichotomous trait. The methodology focuses on the intraclass correlation as the parameter of interest and is analogous to methodology commonly applied to continuous outcome data. For inference problems involving a single sample, confidence interval construction and significance testing are discussed. For two sample problems, test procedures are provided that are an alternative to an approach recently presented by Ramakrishnan et al. [(1992) Genet Epidemiol 9:273–287 (1)]. Two examples based on published data sets are given to illustrate the proposed techniques. ©1995 Wiley-Liss, Inc.     

Midlife Crisis Perceptions,Experiences, Help-Seeking,and Needs Among Multi-Ethnic Malaysian Women

In the present study, researchers explored attitudes toward midlife crises, experience with midlife crises, help-seeking, and needs among multi-ethnic Malaysian women. A total of 14 focus group discussions were conducted with 89 Malaysian women of different ages and socioeconomic backgrounds. Women expressed concern over physical aging and decline in their physical functional health. Having a midlife crisis was frequently reported. Issues that were frequently reported to trigger a midlife crisis, such as empty nest syndrome, impact of aging on sexual and reproductive function, extended parenthood, caring for aging or ill parents, and career challenges were noted by the study participants (listed here in order of most to least frequently reporting of these themes across the group discussions). Overall, these issues were associated with attitudes about aging. A comparatively less open attitude toward sexual attitudes and help-seeking for sexual problems were found among the Malay and Indian women. This may imply that intervention to increase positive attitudes concerning both sexuality and help-seeking intentions should be culturally specific. The use of religious coping for comfort and consolation was frequently reported; therefore, those providing midlife crisis prevention and intervention programs should consider involving faith-based interventions in the Malaysian setting.     

The Role of Social Networks and Support in Postpartum Women's Depression: A Multiethnic Urban Sample

Objectives: This study examined the relationship of social support, and of social networks, to symptoms of depression in a multiethnic sample of women having recently given birth. Methods: Women at community health centers in a Northeastern city were randomly sampled from groups stratified by race/ethnicity (African American, Hispanic, and White) and postpartum interval. Mother's score on the Center for Epidemiologic Studies of Depression Scale (CES-D) was the dependent variable. Main independent variables included the Medical Outcomes Study (MOS) Social Support Survey and a social network item. Univariate statistics assessed the relationship between CES-D score and each of the independent variables. Multivariate linear regression models included core sociodemographic variables alone, the core model with each of the social support and social network variables added separately, and all variables together. We evaluated interactions between race and social support, race and social networks, and social support and social networks. Results: The multivariate models with MOS Social Support and core variables indicated that each 10-point increase in the MOS Social Support Survey was related to a 2.1-unit lower score on the CES-D (95% CI −2.4, −1.7). The inclusion of the social network variable into the core model showed that having two or more friends or family members available was associated with a 13.6-point lower mean score on the CES-D (95% CI −17.5, −9.6), compared to women reporting none or only one available person. Conclusions: Both social support and social networks were statistically significant and independently related to depressive symptomatology.     

Mixed Resilience: A Study of Multiethnic Mexican American Stress and Coping in Arizona

Guided by an integrated framework of resilience, this in‐depth qualitative study examined the major stressors persons of multiethnic Mexican American heritage encountered in their social environments related to their mixed identity and the resilience enhancing processes they employed to cope with these stressors. Life‐story event narratives were transcribed and inductively coded using the constant comparative method. Collectively, the 24 multiethnic Mexican American participants endorsed external supports, interpersonal protective processes, and internal protective processes to navigate stressors associated with monoracism and interethnic discrimination. Findings generated from this study contribute new insight to our understanding of the dynamic interplay of culture and context in resilient processes among mixed heritage individuals. Policy and practice implications for mixed heritage clients and families are discussed.     

Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases

Recently, an increasing number of susceptibility variants have been identified for complex diseases. At the same time, the concern of "missing heritability" has also emerged. There is however no unified way to assess the heritability explained by individual genetic variants for binary outcomes. A systemic and quantitative assessment of the degree of "missing heritability" for complex diseases is lacking. In this study, we measure the variance in liability explained by individual variants, which can be directly interpreted as the locus-specific heritability. The method is extended to deal with haplotypes, multi-allelic markers, multi-locus genotypes, and markers in linkage disequilibrium. Methods to estimate the standard error and confidence interval are proposed. To assess our current level of understanding of the genetic basis of complex diseases, we conducted a survey of 10 diseases, evaluating the total variance explained by the known variants. The diseases under evaluation included Alzheimer's disease, bipolar disorder, breast cancer, coronary artery disease, Crohn's disease, prostate cancer, schizophrenia, systemic lupus erythematosus (SLE), type 1 diabetes and type 2 diabetes. The median total variance explained across the 10 diseases was 9.81%, while the median variance explained per associated SNP was around 0.25%. Our results suggest that a substantial proportion of heritability remains unexplained for the diseases under study. Programs to implement the methodologies described in this paper are available at http://sites.google.com/site/honcheongso/software/varexp.     

Estimating and Testing Pleiotropy of Single Genetic Variant for Two Quantitative Traits

Along with the accumulated data of genetic variants and biomedical phenotypes in the genome era, statistical identification of pleiotropy is of growing interest for dissecting and understanding genetic correlations between complex traits. We proposed a novel method for estimating and testing pleiotropic effect of a genetic variant on two quantitative traits. Based on a covariance decomposition and estimation, our method quantifies pleiotropy as the portion of between‐trait correlation explained by the same genetic variant. Unlike most multiple‐trait methods that assess potential pleiotropy (i.e., whether a variant contributes to at least one trait), our method formulates a statistic that tests exact pleiotropy (i.e., whether a variant contributes to both of two traits). We developed two approaches (a regression approach and a bootstrapping approach) for such test and investigated their statistical properties, in comparison with other potential pleiotropy test methods. Our simulation shows that the regression approach produces correct P‐values under both the complete null (i.e., a variant has no effect on both two traits) and the incomplete null (i.e., a variant has effect on only one of two traits), but requires large sample sizes to achieve a good power, when the bootstrapping approach has a better power and produces conservative P‐values under the complete null. We demonstrate our method for detecting exact pleiotropy using a real GWAS dataset. Our method provides an easy‐to‐implement tool for measuring, testing, and understanding the pleiotropic effect of a single variant on the correlation architecture of two complex traits.     

Teaching Multiethnic Urban Adolescents How to Enhance Their Competencies: Effects of a Middle School Primary Prevention Program on Adaptation

This study evaluated a program that promoted adaptation of students in their first year of secondary school. Participants included 896 multiethnic urban students mostly from socioeconomically disadvantaged families. The program focused on developing healthy self-perceptions, and cognitive, affective and behavioral skills. Multiple regression analyses revealed the predicted positive effects of the program on psychological and social outcomes. However, there was also an unexpected negative outcome for a subgroup of students (11%) made vulnerable by stressful family experiences. These findings broaden our understanding of the effects of such programs and underline the need to address the specific coping competencies of students more at-risk.     

Genetic Analysis Workshop II: pedigree analysis of a binary trait without assuming an underlying liability

A model for concordance in a binary measure that does not rely on the assumption of an underlying latent liability dichotomized about a threshold has been demonstrated for twin pairs [Hannah et al, 1983]. It is extended here to pedigrees of arbitrary structure by making an assumption that is, for small incidence rates, almost equivalent to postulating that relative risks are multiplicative. The model is applied to the workshop data to determine the extent to which the known structure of the simulated models can be recovered.     

Demonstration of a common major gene with pleiotropic effects on immunoglobulin E levels and allergy

Atopic disease is generally recognized to be familial, although specific genetic components have yet to be identified. High levels of a unique class of immunoglobulins, immunoglobulin E (IgE), have been shown to be associated with allergies. Several investigators have reported evidence indicating a recessive regulatory locus where an individual with the homozygous recessive genotype has persistently elevated levels of IgE. Willcox and Marsh [1978] have proposed a hypothesis relating IgE production and liability to become allergic. A test of this hypothesis was carried out in the present study. Bivariate segregation analysis of IgE levels and allergy was performed on 173 nuclear families, and the results indicate that an IgE regulatory locus contributes to the familial transmission of allergy. The results are further discussed in the context of the Willcox and Marsh hypothesis.     

Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases.

We investigate the relevance of the genetic determination of bone mineral density (BMD) variation to that of differential risk to osteoporotic fractures (OF). The high heritability (h(2)) of BMD and the significant phenotypic correlations between high BMD and low risk to OF are well known. Little is reported on h(2) for OF. Extensive molecular genetic studies aimed at uncovering genes for differential risks to OF have focussed on BMD as a surrogate phenotype. However, the relevance of the genetic determination of BMD to that of OF is unknown. This relevance can be characterized by genetic correlation between BMD and OF. For 50 Caucasian pedigrees, we estimated that h(2) at the hip is 0.65 (P < 0.0001) for BMD and 0.53 (P < 0.05) for OF; however, the genetic correlation between BMD and OF is nonsignificant (P > 0.45) and less than 1% of additive genetic variance is shared between them. Hence, most genes found important for BMD may not be relevant to OF at the hip. The phenotypic correlation between high BMD and low risk to OF at the hip (approximately -0.30) is largely due to an environmental correlation (rho(E) = -0.73, P < 0.0001). The search for genes for OF should start with a significant h(2) for OF and should include risk factors (besides BMD) that are genetically correlated with OF. All genes found important for various risk factors must be tested for their relevance to OF. Ideally, employing OF per se as a direct phenotype for gene hunting and testing can ensure the importance and direct relevance of the genes found for the risk of OF. This study may have significant implications for the common practice of gene search for complex diseases through underlying risk factors (usually quantitative traits).