Proper conditional analysis in the presence of missing data: Application to large scale meta-analysis of tobacco use phenotypes.

Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants.

Codevelopment Between Key Personality Traits and Alcohol Use Disorder From Adolescence Through Young Adulthood.

OBJECTIVE: Personality traits related to negative emotionality and low constraint are strong correlates of alcohol use disorder (AUD), but few studies have evaluated the prospective interplay between these traits and AUD symptoms from adolescence to young adulthood. METHOD: The Minnesota Twin Family Study (N = 2,769) was used to examine the developmental interplay between AUD symptoms and three personality measures of constraint, negative emotionality, and aggressive undercontrol from ages 17 to 29. RESULTS: Results from random-intercept, cross-lagged panel models showed that low constraint and aggressive undercontrol predicted subsequent rank-order increases in AUD symptoms from ages 17 to 24. AUD symptoms did not predict rank-order change in these traits from ages 17 to 24. There was support for both cross-effects from ages 24 to 29. Biometric analysis of the twin data showed genetic influences accounted for most of the phenotypic correlations over time. CONCLUSION: Results are consistent with the notion that personality traits related to low constraint and aggressive undercontrol are important vulnerability/predisposition factors for the development of early adult AUD. In later young adulthood, there is more evidence for the simultaneous codevelopment of personality and AUD. Implications are addressed with attention to personality-based risk assessments and targeted AUD prevention approaches.

Aggressive-antisocial boys develop into physically strong young men.

Young men with superior upper-body strength typically show a greater proclivity for physical aggression than their weaker male counterparts. The traditional interpretation of this phenomenon is that young men calibrate their attitudes and behaviors to their physical formidability. Physical strength is thus viewed as a causal antecedent of aggressive behavior. The present study is the first to examine this phenomenon within a developmental framework. We capitalized on the fact that physical strength is a male secondary sex characteristic. In two longitudinal cohorts of children, we estimated adolescent change in upper-body strength using the slope parameter from a latent growth model. We found that males' antisocial tendencies temporally precede their physical formidability. Boys, but not girls, with greater antisocial tendencies in childhood attained larger increases in physical strength between the ages of 11 and 17. These results support sexual selection theory, indicating an adaptive congruence between male-typical behavioral dispositions and subsequent physical masculinization during puberty.

Identity Development in a Transracial Environment: Racial/Ethnic Minority Adoptees in Minnesota.

It has been argued that transracial adopted children have increased risk for problems related to self-esteem and ethnic identity development. We evaluated this hypothesis across four groups of transracial adoptees: Asian (N = 427), Latino (N = 28), Black (N = 6), Mixed/Other (N = 20), and same-race white adoptees (N = 126) from 357 adoptive families. No mean differences were found in adoptee's ratings of affect about adoption, or of curiosity about birthparents. Some differences were found in general identity development and adjustment. There were notable differences in communication about race/ethnicity across groups and between parent and child report.

Developmental trajectories of disordered eating from early adolescence to young adulthood: a longitudinal study.

OBJECTIVE: Research examining changes in eating disorder symptoms across adolescence suggests an increase in disordered eating from early to late adolescence. However, relevant studies have largely been cross-sectional in nature and most have not examined the changes in the attitudinal symptoms of eating disorders (e.g., weight concerns). This longitudinal study aimed to address gaps in the available data by examining the developmental trajectories of disordered eating in females from preadolescence into young adulthood. METHOD: Participants were 745 same-sex female twins from the Minnesota Twin Family Study. Disordered eating was assessed using the Total Score, Body Dissatisfaction subscale, Weight Preoccupation subscale, and a combined Binge Eating and Compensatory Behavior subscale from the Minnesota Eating Behavior Survey assessed at the ages of 11, 14, 18, 21, and 25. Several latent growth models were fit to the data to identify the trajectory that most accurately captures the changes in disordered eating symptoms from 11 to 25 years. RESULTS: The best-fitting models for overall levels of disordered eating, body dissatisfaction, and weight preoccupation showed an increase in from 11 through 25 years. In contrast, bulimic behaviors increased to age of 18 and then stabilized to age of 25. DISCUSSION: The findings expanded upon extant research by investigating longitudinal, symptom specific, within-person changes and showing an increase in cognitive symptoms into young adulthood and the stability of disordered eating behaviors past late adolescence.

Genetic and environmental factors underlying comorbid bulimic behaviours and alcohol use disorders: a moderating role for the dysregulated personality cluster?

Women with bulimia nervosa (BN) frequently have co-occurring alcohol use disorders (AUDs). Studies of shared genetic transmission of these disorders have been mixed. Personality heterogeneity among individuals with BN may explain discrepant findings. Cluster analysis has characterized women with BN in groups on the basis of personality profiles. One group, the Dysregulated cluster, characterized largely by behavioural disinhibition and emotional dysregulation may be more closely linked etiologically to AUDs. This study examined whether genetic associations between BN and AUDs are the strongest among the Dysregulated cluster. Symptoms of BN and AUDs were assessed in female twins at ages 17 and 25 years from the Minnesota Twin Family Study. Personality clusters were defined using the Multidimensional Personality Questionnaire. Twin moderation models suggested small-to-moderate common genetic transmission between BN and AUDs. However, shared genetic effects did not differ by personality cluster. Findings suggest that personality clusters are unlikely to account for inconsistent findings regarding their shared aetiology.

The nature and nurture of high IQ: an extended sensitive period for intellectual development.

IQ predicts many measures of life success, as well as trajectories of brain development. Prolonged cortical thickening observed in individuals with high IQ might reflect an extended period of synaptogenesis and high environmental sensitivity or plasticity. We tested this hypothesis by examining the timing of changes in the magnitude of genetic and environmental influences on IQ as a function of IQ score. We found that individuals with high IQ show high environmental influence on IQ into adolescence (resembling younger children), whereas individuals with low IQ show high heritability of IQ in adolescence (resembling adults), a pattern consistent with an extended sensitive period for intellectual development in more-intelligent individuals. The pattern held across a cross-sectional sample of almost 11,000 twin pairs and a longitudinal sample of twins, biological siblings, and adoptive siblings.

Genetic and environmental contributions to the association between anthropometric measures and iq: a study of Minnesota twins at age 11 and 17.

Associations of height and head circumference with IQ are well documented, but much less is known about the association of IQ with other anthropometric measures or the mechanisms behind these associations. We therefore analyzed the associations between IQ and several anthropometric measures using a twin-study design. Twins born in Minnesota were assessed at either age 11 (756 complete pairs) or 17 (626 complete pairs) and analyzed using genetic modeling. Head circumference and height showed the most consistent positive associations with IQ, whereas more detailed anthropometric measures were not significantly better predictors of IQ. These associations were mainly due to common genetic factors. Our results suggest that the same genetic factors have an effect on physical and cognitive development. Head circumference and height capture information on children's physical development, which is partly associated also with cognitive development.

Lower marriage and divorce rates among twins than among singletons in Danish birth cohorts 1940-1964.

Few studies have examined differences of civil status of twins and singletons and the conclusions are contradictory. In the present study, based on a linkage between the Danish Twin Register, a random 5% sample of the total Danish population, and administrative register databases, the authors compare rates of marriage and divorce in a sample of 35,975 twins and 81,803 singletons born 1940-1964. Cox-regressions are used in order to control for potential confounders. We find that compared with singletons twins have significantly lower marriage rates: (males: 15-19 years: Hazard Ratio (HR) = 0.66 (95%CI: 0.58-0.76); 20-24 years: 0.85 (0.82-0.88); 25 years or more: 0.96 (0.93-0.98) and females: 15-19 years: 0.70 (0.67-0.75); 20-24 years: 0.83 (0.80-0.85); 25 years or more: 0.94 (0.91-0.97)). There is no difference in divorce rates for males, but a significantly lower divorce rate for female twins compared with singletons (HR=0.87, 95%CI: 0.83-0.90). These differences offset each other, thus 57% of both populations remain in their first marriage until censoring. The interpretation may be that since twins have a partner from birth, they do not have the same need for marriage as singletons but have more experience in maintaining a relationship if they do marry.

Is Spousal Similarity for Personality A Matter of Convergence or Selection?

We investigated whether spousal similarity for personality traits results from convergence (i.e., couples becoming more similar to one another over time) or selection (i.e., individuals selecting partners with similar traits) in a sample of 1,296 married couples. Personality was assessed using the Multidimensional Personality Questionnaire. We evaluated whether similarity increased with increasing length of marriage. Evidence of spousal convergence was inconsistent across analyses, arguing against this mechanism as a compelling explanation for spousal similarity. Accordingly, selection processes may better explain spousal similarity in these data. The one exception might be for aggressive aspects of personality.

Association Analysis and Meta-Analysis of Multi-Allelic Variants for Large-Scale Sequence Data.

There is great interest in understanding the impact of rare variants in human diseases using large sequence datasets. In deep sequence datasets of >10,000 samples, ~10% of the variant sites are observed to be multi-allelic. Many of the multi-allelic variants have been shown to be functional and disease-relevant. Proper analysis of multi-allelic variants is critical to the success of a sequencing study, but existing methods do not properly handle multi-allelic variants and can produce highly misleading association results. We discuss practical issues and methods to encode multi-allelic sites, conduct single-variant and gene-level association analyses, and perform meta-analysis for multi-allelic variants. We evaluated these methods through extensive simulations and the study of a large meta-analysis of ~18,000 samples on the cigarettes-per-day phenotype. We showed that our joint modeling approach provided an unbiased estimate of genetic effects, greatly improved the power of single-variant association tests among methods that can properly estimate allele effects, and enhanced gene-level tests over existing approaches. Software packages implementing these methods are available online.

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

A twin study of the genetics of high cognitive ability selected from 11,000 twin pairs in six studies from four countries.

Although much genetic research has addressed normal variation in intelligence, little is known about the etiology of high cognitive abilities. Using data from 11,000 twin pairs (age range = 6-71 years) from the genetics of high cognitive abilities consortium, we investigated the genetic and environmental etiologies of high general cognitive ability (g). Age-appropriate psychometric cognitive tests were administered to the twins and used to create g scores standardized within each study. Liability-threshold model fitting was used to estimate genetic and environmental parameters for the top 15% of the distribution of g. Genetic influence for high g was substantial (0.50, with a 95% confidence interval of 0.41-0.60). Shared environmental influences were moderate (0.28, 0.19-0.37). We conclude that genetic variation contributes substantially to high g in Australia, the Netherlands, the United Kingdom and the United States.

Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population.

BACKGROUND: Depressed mood is a major concern in the elderly, with consequences for morbidity and mortality. Previous studies have demonstrated that genetic factors in depression and subsyndromal depressive symptoms are no less important in the elderly than during other life stages. Variations in genes included in the serotonin system have been suggested as risk factors for various psychiatric disorders but may also serve as candidates for normal variations in mood. METHODS: This study included 684 elderly Danish twins to investigate the influence of 11 polymorphisms in 7 serotonin system genes on the mean level of depression symptomatology assessed over several years, reflecting individuals' underlying mood level. RESULTS: A suggestive association of sequence variations in genes responsible for the synthesis (TPH), recognition (5-HTR2A), and degradation (MAOA) of serotonin with depression symptomatology was found, although the effect was generally restricted to men. We also found that a specific haplotype in VMAT2, the gene encoding the vesicular monoamine transporter, was significantly associated with depression symptoms in men (p= .007). CONCLUSIONS: These results suggest that variations in genes encoding the components of serotonin metabolism may influence the basic mood level and that different genetic factors may apply in men and women.

P3 event-related potential amplitude and the risk for disinhibitory disorders in adolescent boys.

BACKGROUND: The children of parents who abuse alcohol typically show reduced amplitude of the P3 event-related potential wave. We determined if this effect was present in a population-based sample of older adolescent boys, whether it was associated with paternal antisocial personality and drug use, and whether it appeared in youth with childhood externalizing and substance use disorders. METHODS: A statewide sample of 502 male youth, identified from Minnesota birth records as members of twin pairs, had their P3 amplitude measured, using a visual oddball paradigm when they were approximately 17 years old. Structured clinical interviews covering attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, antisocial personality disorder, and substance use disorders were administered in person to the youth and his parents at the time of the P3 assessment and again to the youth 3 years later. RESULTS: Reduced P3 was associated with disorders and paternal risk for disorders, reflecting a behavioral disinhibition spectrum that included attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, antisocial personality disorder, alcoholism, nicotine dependence, and illicit drug abuse and dependence. Reduced P3 at age 17 predicted the development of substance use disorders at age 20. Most effect sizes associated with these group differences exceeded 0.70, indicating medium to moderately large group differences. Maternal alcoholism and substance use during pregnancy were unrelated to P3 amplitude in offspring. CONCLUSION: Small amplitude P3 may indicate genetic risk for a dimension of disinhibiting psychiatric disorders, including childhood externalizing, adult antisocial personality disorder, and substance use disorders.

Alcohol use disorder in women: Risks and consequences of an adolescent onset and persistent course.

Women are more vulnerable to the deleterious effects of both acute and protracted alcohol use than men, but women's lower levels of alcohol consumption and alcohol use disorder (AUD) have resulted in a paucity of investigations on the development of alcohol problems in women. In particular, it is not clear to what extent the cascading effects of key etiological factors that contribute to an especially severe course of AUD in men also underlie the development of AUD in women. To fill this gap, we examined the adolescent risk factors and adult consequences associated with an adolescent onset and persistent course of AUD in a community sample of women (n = 636) from ages 17 to 29. Women with AUD exhibited greater psychopathology and psychosocial impairment than those without, with an adolescent onset and persistent course indicative of the greatest severity. Notably, high levels of impairment across all women with AUD reduced the utility of onset and course to differentiate profiles of risk and impairment. In contrast to previous work in men, even women whose AUD symptoms desisted continued to exhibit impairment, suggesting that an adolescent onset of AUD is associated with enduring consequences for women's health and functioning, even after ostensible "recovery."

Quantifying the Association between Personality Similarity and Marital Adjustment Using Profile Correlations: A Cautionary Tale.

Profile correlations are sometimes used to quantify personality trait similarity between relationship partners. These coefficients are then used to test whether similar couples are happier couples. The current paper describes several different methods of calculating profile correlations and outlines procedures for testing whether these coefficients are related to marital adjustment in a sample of 1,643 couples. There was little evidence that profile correlations were related to marital adjustment after accounting for normativeness (i.e., the degree to which individual's matched the typical personality profile) and when accounting for each individual's personality attributes. Results suggest that researchers using profile correlations should be cautious given that the interpretation and psychological meaning of results often depend on how the coefficients are calculated.

The dysregulated cluster in personality profiling research: longitudinal stability and associations with bulimic behaviors and correlates.

Among cluster analytic studies of the personality profiles associated with bulimia nervosa, a group of individuals characterized by emotional lability and behavioral dysregulation (i.e., a dysregulated cluster) has emerged most consistently. However, previous studies have all been cross-sectional and mostly used clinical samples. This study aimed to replicate associations between the dysregulated personality cluster and bulimic symptoms and related characteristics using a longitudinal, population-based sample. Participants were females assessed at ages 17 and 25 from the Minnesota Twin Family Study, clustered based on their personality traits. The Dysregulated cluster was successfully identified at both time points and was more stable across time than either the Resilient or Sensation Seeking clusters. Rates of bulimic symptoms and related behaviors (e.g., alcohol use problems) were also highest in the dysregulated group. Findings suggest that the dysregulated cluster is a relatively stable and robust profile that is associated with bulimic symptoms.

A growth curve model with fractional polynomials for analysing incomplete time-course data in microarray gene expression studies.

Identifying the various gene expression response patterns is a challenging issue in expression microarray time-course experiments. Due to heterogeneity in the regulatory reaction among thousands of genes tested, it is impossible to manually characterize a parametric form for each of the time-course pattern in a gene by gene manner. We introduce a growth curve model with fractional polynomials to automatically capture the various time-dependent expression patterns and meanwhile efficiently handle missing values due to incomplete observations. For each gene, our procedure compares the performances among fractional polynomial models with power terms from a set of fixed values that offer a wide range of curve shapes and suggests a best fitting model. After a limited simulation study, the model has been applied to our human in vivo irritated epidermis data with missing observations to investigate time-dependent transcriptional responses to a chemical irritant. Our method was able to identify the various nonlinear time-course expression trajectories. The integration of growth curves with fractional polynomials provides a flexible way to model different time-course patterns together with model selection and significant gene identification strategies that can be applied in microarray-based time-course gene expression experiments with missing observations.

Puberty and the genetic diathesis of disordered eating attitudes and behaviors.

Twin studies from the Minnesota Twin Family Study (MTFS) suggest negligible genetic effects on eating pathology before puberty but increased genetic effects during puberty. However, an independent study found no pubertal differences in genetic and environmental effects (R. Rowe, A. Pickles, E. Simonoff, C. M. Bulik, & J. L. Silberg, 2002). Discrepant results may be due to methodological differences. The MTFS studies divided twins at mid-puberty, whereas R. Rowe et al. (2002) divided twins based on menarche alone. In the present study, the authors aimed to reconcile discrepant findings by examining differences in etiologic effects for disordered eating attitudes and behaviors (i.e., levels of weight preoccupation, body dissatisfaction, binge eating, compensatory behaviors) using both classification methods in a new sample of 656 female twins. Using the MTFS method (i.e., K. L. Klump, M. McGue, & W. G. Iacono, 2003), the authors observed nominal genetic effects in prepubertal twins but significant genetic effects in pubertal and young adult twins. Conversely, genetic effects were moderate and equal in all groups using the R. Rowe et al. (2002) method. Findings highlight the potentially important role of puberty in the genetic diathesis of disordered eating attitudes and behaviors and the need to use early indicators of pubertal status in studies of developmental effects.