Longitudinal Genetic Analysis Research Articles

Analysis of Growth Trajectories and Verification of Related SNPs in Populus deltoides.

As an important timber genus with high economic and ecological values, Populus is a model for dissecting the genetic architecture of growth traits in perennial forest trees. However, the genetic mechanisms of longitudinal growth traits in poplar remain incompletely understood. In this study, we conducted longitudinal genetic analysis of height and diameter at breast height (DBH) in eleven-year poplar clones using ultra-deep sequencing datasets. We compared four S-shaped growth models, including asymptotic, Gompertz, logistic, and Richard, on eleven-year height and DBH records in terms of five metrics. We constructed the best-fitting growth model (Richard) and determined poplar ontogenetic stages by virtue of growth curve fitting and likelihood ratio testing. This study provides some scientific clues for temporal variation of longitudinal growth traits in Populus species.

Longitudinal genetic analysis for Pacific abalone growth-related traits in sea-based culture system

Pedigreed family-based selective breeding is an appealing approach in genetic improvement of aquaculture species as the benefits can be cumulative and permanent. To determine the longitudinal growth characteristics of Pacific abalone (Haliotis discus hannai), shell colour rings were manipulated by feeding alternative algae, and shell length (SL) identification was performed at different ages. Eight SL records were obtained from 3147 individuals in 192 full-sib families at 6, 7, 9, 13, 18, 24, 28, and 32 months after hatching. To estimate the additive genetic and environmental variance components, longitudinal genetic analysis of repeated SL measurements was conducted using multivariate, auto-regressive, antedependence and random regression models with restricted maximum likelihood method. The results showed that the multivariate model with common full-sib family variance and residual heterogeneity of variance was the best model for the given dataset. Heritability estimates showed a decreasing trend with age, which is similar to the results obtained from the quadratic polynomial random regression model, and ranged from 0.629 at 9 months to 0.259 at 32 months. The separate rearing and tagging of single abalone at 6 months may have led to significant common environment family bias and overestimation of heritability. The antedependence model did not achieve a better fit for the obtained dataset. Estimates of genetic correlation between contiguous ages were high, ranging from 0.622 between 6 and 32 months to 0.987 between 28 and 32 months. The results demonstrated that genetic gain can be obtained in selection for Pacific abalone growth and outlined information regarding the age at which selection should be performed. This study can provide data and guidelines to a Pacific abalone selection program for growth related-traits.

Longitudinal genetic analysis of semen production traits in Holstein bulls according to a random regression animal models on age.

Here we used random regression animal models (RRAMs) to investigate genetic change over age in the semen volume (VOL) and sperm concentration (CON) of Holstein bulls. We used 35,294 collection records from 1284 Holstein bulls and their 4166 pedigree records. The models included year and month of collection, collection place, collection method, and number of collections attempted for each day and month of age (second-order regressions) as fixed effects; technician as a random effect; and additive genetic and permanent environment as random regressions (first-order regressions). We examined two RRAMs with homogeneous and heterogeneous residual variances (RRAM1 and RRAM2, respectively). By using RRAM1, heritability for VOL and CON increased from 0.08 to 0.61 and 0.18 to 0.57, respectively, between 10 and 126 months of age. By using RRAM2, heritability for VOL increased from 0.11 to 0.28 between 10 and 24 months of age for young bulls and increased from 0.08 to 0.48 between 25 and 126 months of age for mature bulls; heritability for CON ranged from 0.18 to 0.19 for young bulls and increased from 0.10 to 0.48 for mature bulls. Posterior genetic correlations between young ages and older ages were strongly positive for VOLs but weak for CONs.

Longitudinal genetic analysis of growth-related traits in red swamp crayfish Procambarus clarkii (Girard)

Longitudinal genetic analysis of growth-related traits in red swamp crayfish Procambarus clarkii (Girard)

Early queen joining and long-term queen associations in polygyne colonies of an invasive wasp revealed by longitudinal genetic analysis.

Invasive social insects rank among the most damaging of terrestrial species. They are responsible for extensive damage and severely threaten the biodiversity of environments where they are introduced. Variation in colony social form commonly occurs in introduced populations of yellowjacket wasps (genus Vespula). In particular, invasive colonies may contain multiple queens (i.e., polygyne) and persist several years, while in the native range, the colonies are usually annual and harbor a single queen (i.e., monogyne). In this study, we used genome‐wide loci obtained by double digest restriction site‐associated DNA sequencing (RADseq) to investigate the genetic structure and queen turnover in colonies of the western yellowjacket, Vespula pensylvanica, in their introduced range in Hawaii. Of the 27 colonies monitored over four months (October–January), 19 were polygyne and already contained multiple queens on the first day of sampling. Contrary to previous speculation, this finding suggests that polygyny often arises early in the annual colony cycle, before the production of new queens in the fall. Furthermore, polygyne colonies exhibited a prolonged average lifespan relative to those headed by a single queen. As a result, there is no clear window during which colony eradication efforts would be more effective than upon first discovery. The relatedness among nestmate queens was slightly above zero, indicating that these colonies are generally composed of nonrelatives. The queen turnover within each colony was low, and we detected some full‐sibling workers sampled up to four months apart. Finally, we did not detect any population structure among colonies, suggesting that queens disperse up to several kilometers. Taken together, our results provide the first insights into the requeening dynamics in this invasive and incipiently polygyne population and illuminate the early establishment of multiple long‐lasting queens in these damaging colonies.

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4−/CD8− (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4−/CD8− cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8+ cases exhibited structural alterations involving the 3′ untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4−/CD8− disease showed a type-2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases.

Longitudinal genetic analysis for growth traits in the complete diallel cross of rainbow trout (Oncorhynchus mykiss)

A complete diallel cross involving the five strains from Bohai, Denmark, Donaldson, Norway and California and self-breeding within each strain were carried out to evaluate general combining ability, specific combining ability, reciprocal, maternal, linebred effects and heterosis for two growth traits in rainbow trout. To estimate the changes in various genetic and permanent environment effects, longitudinal genetic analysis was employed and implemented with restricted maximum likelihood (REML) method. Using Bayesian information criterion (BIC), the longitudinal genetic model with linear genetic effects and Legendre polynomial of order 2 for permanent environment effects was chosen as the optimal one for body length, whereas genetic effects were constant for body weight. Significance tests for regression effects show that for body length, there were 11 genetic effects changing with growth time. Among all cross combinations, the specific combining ability between Bohai and Donaldson was the smallest across the measuring period. No genetic effect was found to be consistently high or low between the two analyzed traits.

Long-Term Parvovirus B19 Infections With Genetic Drift After Cord Blood Transplantation Complicated by Persistent CD4+ Lymphocytopenia

A 5-month-old girl was diagnosed with Langerhans cell histiocytosis and received unrelated umbilical cord blood transplantation at the age of 14 months. After cord blood transplantation, CD4(+) lymphocytopenia from unknown causes was observed, and persistent infections with human parvovirus B19 (B19) occurred. We performed repeated longitudinal genetic analysis for B19, which revealed 6 nucleotide mutations in B19 nonstructural protein regions in the patient. The resulting changes of the nonstructural 1 structure may have altered antigenicity of the virus and could play a role in the pathogenesis of persistent infection under immunocompromised conditions.

A discussion of gene–gene and gene–environment interactions and longitudinal genetic analysis of complex traits

A discussion of gene–gene and gene–environment interactions and longitudinal genetic analysis of complex traits

Longitudinal Association Analysis of Quantitative Traits

Longitudinal genetic studies provide a valuable resource for exploring key genetic and environmental factors that affect complex traits over time. Genetic analysis of longitudinal data that incorporate temporal variations is important for understanding genetic architecture and biological variations of common complex diseases. Although they are important, there is a paucity of statistical methods to analyze longitudinal human genetic data. In this article, longitudinal methods are developed for temporal association mapping to analyze population longitudinal data. Both parametric and nonparametric models are proposed. The models can be applied to multiple diallelic genetic markers such as single-nucleotide polymorphisms and multiallelic markers such as microsatellites. By analytical formulae, we show that the models take both the linkage disequilibrium and temporal trends into account simultaneously. Variance-covariance structure is constructed to model the single measurement variation and multiple measurement correlations of an individual based on the theory of stochastic processes. Novel penalized spline models are used to estimate the time-dependent mean functions and regression coefficients. The methods were applied to analyze Framingham Heart Study data of Genetic Analysis Workshop (GAW) 13 and GAW 16. The temporal trends and genetic effects of the systolic blood pressure are successfully detected by the proposed approaches. Simulation studies were performed to find out that the nonparametric penalized linear model is the best choice in fitting real data. The research sheds light on the important area of longitudinal genetic analysis, and it provides a basis for future methodological investigations and practical applications.

Longitudinal genetic analysis of anxiety sensitivity.

Anxiety sensitivity is associated with both anxiety and depression and has been shown to be heritable. Little, however, is known about the role of genetic influence on continuity and change of symptoms over time. The authors' aim was to examine the stability of anxiety sensitivity during adolescence. By using a genetically sensitive design, the authors were also able to investigate the extent to which genetic and environmental factors influence anxiety sensitivity over time. Self-reports of anxiety sensitivity were obtained for over 1,300 twin and sibling pairs at 3 time points. Data were analyzed using multivariate genetic models. Anxiety sensitivity was moderately heritable at all time points with substantial nonshared environmental contributions. Time 1 genetic factors accounted for continuity of symptoms at Times 2 and 3. New genetic factors at Time 2 also influenced Time 3 symptoms. New nonshared environmental influences emerged at each time point. Analysis of a latent factor of trait anxiety sensitivity revealed some stable nonshared environmental influences. Genetic effects were generally stable over time, with new genetic influences emerging in late adolescence. Environmental influences on anxiety sensitivity were, on the whole, more time specific; however, some stable environmental influences were also found.

Association of Four Genetic Loci with Uric Acid Levels and Reduced Renal Function: The J-SHIPP Suita Study

Background: Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross-sectional and longitudinal genetic epidemiological analysis. Methods: The study enrolled 5,165 Japanese subjects aged 64 ± 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups. Results: Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 ± 1.6, 5.0 ± 1.4, 5.3 ± 1.4 mg/dl; p = 7.6 × 10^–20), SLC2A9 rs1014290 (TT/TG/GG: 4.9 ± 1.4, 5.1 ± 1.4, 5.3 ± 1.4 mg/dl; p = 3.1 × 10^–11) and ABCG2 rs2231142 (TT/TG/GG: 5.3 ± 1.5, 5.2 ± 1.4, 5.1 ± 1.4 mg/dl; p = 2.0 × 10^–5) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97–53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 ± 1.7, 3.6 ± 1.0, 5.2 ± 1.4 mg/dl; p = 9.3 × 10^–82). However, these subjects showed significantly reduced renal function (β = –0.111; p < 0.001) independently of possible covariates. Conclusion: Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function.

Longitudinal genetic analysis of brain volumes in normal elderly male twins

This study investigated the role of genetic and environmental influences on individual differences in brain volumes measured at 2 time points in normal elderly males from the National Heart, Lung, and Blood Institute Twin Study. The magnetic resonance imaging (MRI) scans were conducted 4 years apart on 33 monozygotic and 33 dizygotic male twin pairs, aged 68 to 77 years when first scanned. Volumetric measures of total brain and total cerebrospinal fluid were significantly heritable at baseline (over 70%). For both volumes genetic influences at follow-up were entirely accounted for by genetic influences at baseline, suggesting that the same genetic factors influence variability in brain volume at each time of assessment. Variability in 4-year volume change was due to shared and individual-specific environmental influences. There was little evidence for heritable influences on change measures. These results suggest that variation in longitudinal change of some brain volume measures may have different underlying genetic and environmental architecture from variation in repeat cross-sectional measures, which could have implications for intervention strategies for age-related illness associated with brain morphology. The results of this study are discussed in the context of the small sample size and associated limitations of statistical power.

Longitudinal Genetic Analysis for Loneliness in Dutch Twins

In previous studies we obtained evidence that variation in loneliness has a genetic component. Based on adult twin data, the heritability estimate for loneliness, which was assessed as an ordinal trait, was 48%. These analyses were done on loneliness scores averaged over items ('I feel lonely' and 'Nobody loves me') and over time points. In this article we present a longitudinal analysis of loneliness data assessed in 5 surveys (1991 through 2002) in Dutch twins (N = 8389) for the two separate items of the loneliness scale. From the longitudinal growth modeling it was found sufficient to have non-zero variance for the intercept only, while the other effects (linear, quadratic and cubic slope) had zero variance. For the item 'I feel lonely' we observed an increasing age trend up to age 30, followed by a decline to age 50. Heritability for individual differences in the intercept was estimated at 77%. For the item 'Nobody loves me' no significant trend over age was seen; the heritability of the intercept was estimated at 70%.

Longitudinal Genetic Analysis of Internalizing and Externalizing Problem Behavior in Adopted Biologically Related and Unrelated Sibling Pairs

To obtain a better understanding of how genetic and environmental processes are involved in the stability and change in problem behavior from early adolescence into adulthood, studies with genetically informative samples are important. The present study used parent-reported data on internalizing and externalizing problem behavior of adoptees at mean ages 12.4, 15.5 and 26.3. In this adoption study adopted biologically related sibling pairs shared on average 50% of their genes and were brought up in the same family environment, whereas adopted biologically unrelated sibling pairs only shared their family environment. The resemblance between these adopted biologically related (N = 106) and unrelated sibling pairs (N=230) was compared and examined over time. We aimed to investigate (1) to what extent are internalizing and externalizing problem behavior stable from early adolescence into adulthood, and (2) whether the same or different genetic and environmental factors affect these problem behaviors at the 3 assessments. Our results show that both internalizing (rs ranging from .34 to .58) and externalizing behavior (rs ranging from .47 to .69) were rather stable over time. For internalizing and externalizing problem behavior it was found that both genetic and shared environmental influences could be modeled by an underlying common factor, which explained variance in problem behavior from early adolescence into adulthood and accounted for stability over time. The nonshared environmental influences were best modeled by a Cholesky decomposition for internalizing behavior, whereas a time-specific influence of the nonshared environment was included in the final model of externalizing behavior.

SES and CHAOS as environmental mediators of cognitive ability: A longitudinal genetic analysis

This study examined shared environmental influences on the longitudinal stability of general cognitive ability, as mediated by socioeconomic status and chaos in the home, using 287 pairs of elementary school-age twins drawn from the Western Reserve Reading Project (WRRP). General cognitive ability was evaluated at two annual assessments using the Stanford-Binet Intelligence Test. SES was examined using the highest level of education achieved by the mother of the twins, and chaos by a 6-item parent-report questionnaire. Results suggest that SES and CHAOS not only account for independent sources of shared environmental influences related to general cognitive ability at a given measurement occasion, but these effects also account for a portion of the longitudinal stability of general cognitive ability in early childhood.

Longitudinal genetic analysis of executive function in elderly men

The objective of this study was to characterize the relative contribution of genetic and environmental influences to individual differences in longitudinal performance and decline of executive function (EF) using a population-based prospective study of male, WWII veteran twins (NHLBI twin study). Three tests of EF were administered when the twins were 59–70 years old, with 9- and 13-year follow-up. APOE ɛ4 allele status was incorporated in the genetic models to determine its contribution to longitudinal genetic variability. Mean EF performance significantly worsened over time. EF performance was highly genetically correlated across repeat assessment. There were significant genetic influences on 9- and 13-year decline in digit symbol performance. For all tasks decline over the last 4-year follow-up was influenced by individual-specific environmental effects. Controlling for APOE ɛ4 allele presence did not appreciably change the magnitude of genetic effects. These results suggest that common genetic factors underlie longitudinal EF task performance. Genetic influences on EF decline, however, appear to be evident at longer time intervals between assessments.

Longitudinal Genetic Analysis of Early Reading: The Western Reserve Reading Project

We examined the genetic and environmental contribution to the stability and instability of reading outcomes in early elementary school using a sample of 283 twin pairs drawn from the Western Reserve Reading Project. Twins were assessed across two measurement occasions. In Wave 1, children were either in kindergarten or first grade. Wave 2 assessments were conducted one year later. Results suggested substantial genetic stability across measurement occasions. Additionally, shared environmental influences also accounted for stability, particularly for variables more closely tied to direct instruction such as phonological awareness, letter knowledge, and word knowledge. There was also evidence for independent genetic and shared environmental effects, suggesting that new sources of variance may emerge as the demands of school change and children begin to acquire early reading skills.

Continuity and Change in Preschool ADHD Symptoms: Longitudinal Genetic Analysis with Contrast Effects

The genetic and environmental mediation of continuity and change in parent-reported ADHD symptoms were investigated in a cohort of over 6000 twin pairs at 2, 3 and 4 years of age. Genetic analyses of the cross-sectional data yielded heritability estimates of 0.78-0.81 at each age, with contrast effects. A common pathway model provided the best fit to the longitudinal data, indicating that genetic influences underlie 91% of the stable variance in ADHD symptomatology. In other words, what is stable for ADHD symptoms is largely genetic. Contrast effects acting in the same direction at different ages contributed to the observed continuity:longitudinal correlations were greater for dizygotic than monozygotic twins.

The Genetics of Middle-Age Spread in Middle-Class Males

This study provides findings to assist in identifying factors that contribute to the current clinical and public health debate of the obesity epidemic. The study examined the genetics of adult-onset weight change in middle-aged male—male twins controlling for weight in early adulthood, lifetime history of tobacco use and alcohol dependence, and aimed to estimate the proportion of genetic factors that influence weight change between early adulthood and middle age in white middle-class males. The study was a classic longitudinal twin design and used Body Mass Index (BMI) for three waves of data collection from the Vietnam Era Twin Registry — induction physicals (∼ 1968), 1987 and 1990 — or periods corresponding between young adulthood and middle age. Univariate heritability estimates for BMI at all three data periods were conducted as well as a Cholesky longitudinal genetic analysis for weight change controlling for BMI at military induction, smoking and alcohol use. Frequency data indicated that the sample was on average classified as normal BMI in their 20s; but BMI gradually increased during the next twenty years. Univariate data for each data period indicated that additive genetic factors accounted for between 63% and 69% of total variance in BMI. The Cholesky longitudinal genetic analysis of BMI87 and BMI90, controlling for BMI at military induction, indicated that more than half of the change in BMI from early adulthood to middle age remains heritable. No shared environmental factors were identified, thus the remainder of the variance was accounted for by nonshared, or unique, environmental factors and error. The data analysis suggests that treatments and public health interventions need to recognize the magnitude of genetic factors if short-term and long-term interventions are to be effective.