Sequential Oligogenic Linkage Analysis Routines Research Articles

Sex-specific differences in the genetic and environmental effects on cardiac phenotypic variation assessed by echocardiography

The drivers of sexual dimorphism in heart failure phenotypes are currently poorly understood. Divergent phenotypes may result from differences in heritability and genetic versus environmental influences on the interplay of cardiac structure and function. To assess sex-specific heritability and genetic versus environmental contributions to variation and inter-relations between echocardiography traits in a large community-based cohort. We studied Framingham Heart Study participants of Offspring Cohort examination 8 (2005–2008) and Third Generation Cohort examination 1 (2002–2005). Five cardiac traits and six functional traits were measured using standardized echocardiography. Sequential Oligogenic Linkage Analysis Routines (SOLAR) software was used to perform singular and bivariate quantitative trait linkage analysis. In our study of 5674 participants (age 49 ± 15 years; 54% women), heritability for all traits was significant for both men and women. There were no significant differences in traits between men and women. Within inter-trait correlations, there were two genetic, and four environmental trait pairs with sex-based differences. Within both significant genetic trait pairs, men had a positive relation, and women had no significant relation. We observed significant sex-based differences in inter-trait genetic and environmental correlations between cardiac structure and function. These findings highlight potential pathways of sex-based divergent heart failure phenotypes.

Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children

Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion. We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort. We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members. All 3 parameters were significantly heritable (h2=0.22-0.78; P<0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glycine decarboxylase (GLDC) and for glycine with GLDC (P<3.5×10-8; effect sizes, 0.03-0.07). No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant associations between the serine-glycine ratio and rs2886059 (β = 0.68; SE, 0.25; P=0.006) and rs3796191 (β = 0.25; SE, 0.08; P=0.003) and between glycine and rs3796191 (β = -0.08; SE, 0.02; P=0.0004). These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures (P<0.006). Significant genetic and phenotypic correlations were found for glycine and the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P<0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P<0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes. Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.

Heritability of musculoskeletal pain and pain sensitivity phenotypes: 2 generations of the Raine Study.

There is a need to better understand biological factors that increase the risk of persistent musculoskeletal (MSK) pain and heightened pain sensitivity. Knowing the heritability (how genes account for differences in people's traits) can enhance the understanding of genetic vs environmental influences of pain and pain sensitivity. However, there are gaps in current knowledge, including the need for intergenerational studies to broaden our understanding of the genetic basis of pain. Data from Gen1 and Gen2 of the Raine Study were used to investigate the heritability of MSK pain and pressure and cold pain sensitivity. Participants included parents (Gen1, n = 1092) and their offspring (Gen2, n = 688) who underwent a battery of testing and questionnaires including pressure and cold pain threshold testing and assessments of physical activity, sleep, MSK pain, mental health, and adiposity. Heritability estimates were derived using the Sequential Oligogenic Linkage Analysis Routines software. Heritability estimates for MSK pain and pressure pain sensitivity were significant, accounting for between 0.190 and 0.289 of the variation in the phenotype. By contrast, heritability of cold pain sensitivity was not significant. This is the largest intergenerational study to date to comprehensively investigate the heritability of both MSK pain and pain sensitivity, using robust statistical analysis. This study provides support for the heritability of MSK pain and pain sensitivity to pressure, suggesting the need for further convergence of genetic and environmental factors in models for the development or maintenance of these pain disorders.

P-wave signal-averaged electrocardiography: Reference values, clinical correlates, and heritability in the Framingham Heart Study

BackgroundP-wave signal-averaged electrocardiography (P-SAECG) quantifies atrial electrical activity. P-SAECG measures and their clinical correlates and heritability have had limited characterization in community-based cohorts.ObjectiveThe purpose of this study was to (1) establish reference values; (2) identify clinical risk factors associated with P-SAECG; and (3) estimate genetic heritability for P-SAECG traits.MethodsWe performed P-SAECG in 2 generations of Framingham Heart Study participants. We performed backward elimination regression models to assess associations of clinical factors with each SAECG trait (P-wave [PW] duration, root mean square voltage in terminal 40 ms [RMS40], terminal 30 ms RMS30, terminal 20 ms RMS20, RMS PW, and PW integral). We estimated the adjusted genetic heritability of P-SAECG measures using the Sequential Oligogenic Linkage Analysis Routines (SOLAR) program.ResultsWe included 4307 participants (age 55 ± 14 years; 56% female). The reference values were derived from 1752 participants without cardiovascular risk factors. Median (2.5th percentile; 97.5th percentile) total PW duration was 118 ms (93; 146) in women and 128 ms (104; 158) in men in the reference sample, and 121 ms (94; 151) in women and 129 ms (103; 159) in the entire study cohort (broad sample). In the broad sample, after adjusting for age and sex, total PW duration was positively associated with height, weight, prevalent heart failure, history of atrial fibrillation (AF), and atrioventricular node blockers, and negatively associated with smoking, waist circumference, heart rate, and diabetes. The estimated heritability of P-SAECG traits was moderate, ranging from 11.9% for RMS30 to 24.9% for PW integral.ConclusionP-SAECG traits are associated with multiple AF-related risk factors and are moderately heritable.

Gene-Environment Joint Linkage and Association Analysis of Arsenic Exposure and Diabetes-Related Traits in the Strong Heart Family Study

BACKGROUND AND AIM: Inorganic arsenic exposure is of increasing interest as a possible risk factor for diabetes, and although there is growing research on potential toxicological mechanisms, the biology remains incompletely understood. METHODS: This is a cross-sectional, gene-environment interaction study using data from n=1,915 participants from 40 pedigrees in the Strong Heart Family Study with measured arsenic exposure (sum of inorganic and methylated urine arsenic species, dichotomized for analysis), age, sex, educational attainment, body mass index, genotypes, family relationships, fasting glucose, HOMA-IR, and HOMA-B. We conducted a multipoint variance components linkage analysis testing for arsenic-locus interactions (GxE) predicting glucose, HOMA-IR, or HOMA-B in separate models, adjusted for potential confounders of the arsenic-outcome relationships. We then tested for SNP-trait associations and SNP GxE in linkage regions. Analyses were implemented using the software Sequential Oligogenic Linkage Analysis Routines (SOLAR). RESULTS:We localized three quantitative trait loci that showed suggestive evidence for differential genetic contributions to the outcome in the presence of higher vs. lower inorganic arsenic exposure. The first was an interaction locus for fasting glucose at chromosome 17q22 (LOD 2.6 in GxE model, LOD 1.5 in standard linkage model without interaction). The second was an interaction locus for HOMA-IR at chromosome 7p13 (LOD 2.0 in GxE model, 0.4 in the standard linkage model). The third was an interaction locus for HOMA-B at chromosome 18q22.2 (LOD 2.0 in GxE model, LOD 1.7 in standard linkage model). Several SNPs showed Bonferroni-significant associations with diabetes-related traits, with the strongest evidence for rs4793861 in the MSI2 gene for glucose; however, no tested SNPs showed Bonferroni-significant interactions with arsenic. CONCLUSIONS:We found suggestive evidence for different locus-specific contributions to diabetes trait variability in the presence of higher inorganic arsenic exposure, and SNPs in these regions that were associated with diabetes traits. Further research (e.g., linkage fine-mapping) might further elucidate this biology. KEYWORDS: Environmental Epidemiology, Toxicology, Heavy Metals

768 The Relationship Between Circadian Rhythm and Autism Spectrum Disorder Traits and Executive Function Across the Life Span

Abstract Introduction Children and adults with autism spectrum disorder (ASD) often have sleep, circadian, and executive function impairments, which can affect daytime quality. Yet, the relationship between sleep or circadian traits and ASD traits is still unknown. Thus, we aimed to determine if sleep and circadian traits were associated with ASD traits, including executive function. Methods We studied data from participants with and without ASD enrolled in the family-based study Autism Spectrum Program of Excellence (ASPE), University of Pennsylvania. We used GGIR to analyze actigraphy-derived sleep and circadian traits from 250 participants (219 adults ages 18–87 years, mean 44.2 ± 17.3 years; 31 children ages 4–17 years, mean 11.3 ± 3.9 years). These traits were compared to ASD traits (social impairment and restricted/repetitive behavior via Social Responsiveness Scale, Second Edition) and executive function (Behavior Rating Inventory of Executive Function) using linear multivariate regression models adjusted for age, age2, and sex via Sequential Oligogenic Linkage Analysis Routines. Results In adults, earlier start time of the 10 hours of highest activity in a 24-hour day (M10 start time; p = 0.02), decreased robustness of the rest/activity rhythm (relative amplitude; p = 0.03), and increased intradaily variability of rest/activity rhythm (p = 0.04) were associated with more social impairment. In children, earlier M10 start time (p = 0.02) and decreased relative amplitude (p = 0.03) were associated with more social impairment. In adults, higher average 5-hour period of lowest activity in a 24-hour day (L5 average; p = 0.03), lower average 10-hour period of highest activity in a 24-hour day (M10 average; p = 0.005), earlier M10 start time (p = 0.02), decreased relative amplitude (p = &amp;lt;0.001), increased intradaily variability (p = &amp;lt;0.001) and decreased sleep efficiency (p = 0.04) were associated with increased executive function impairment. In children, earlier M10 start time (p = 0.006) and intradailty variability (p = 0.008) were associated with increased executive function impairment. Conclusion Circadian traits are significantly associated with ASD traits, including executive function, suggesting the importance of sleep-wake rhythm dysfunction in ASD. Support (if any) Anonymous donor; NIH T32HL07713; University of Pennsylvania’s Institute for Translational Medicine and Therapeutics

Heritable anisotropy associated with cognitive impairments among patients with schizophrenia and their non-psychotic relatives in multiplex families.

To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438). We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections. Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts. Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.

Estimating the Heritability of Developmental Change in Neural Connectivity, and Its Association With Changing Symptoms of Attention-Deficit/Hyperactivity Disorder

BackgroundTwin studies show that age-related change in symptoms of attention-deficit/hyperactivity disorder (ADHD) is heritable. However, we do not know the heritability of the development of the neural substrates underlying the disorder. Here, we estimated the heritability of developmental change in white matter tracts and the brain’s intrinsic functional connectivity using longitudinal data. We further determined associations with change in ADHD symptoms. MethodsThe study reports on 288 children, which included 127 siblings, 19 cousins, and 142 singletons; 150 (52%) had a diagnosis of ADHD (determined by clinician interview with parent); 188 were male. All had two clinical assessments (overall baseline mean age: 9.4 ± 2.4 years; follow-up: 12.5 ± 2.6 years). Diffusion tensor imaging estimated microstructural properties of white matter tracts on 252 participants. Resting-state functional magnetic resonance imaging estimated intrinsic connectivity within and between major brain networks on 226 participants. Total additive genetic heritability (h2) of the annual rate of change in these neural phenotypes was calculated using SOLAR (Sequential Oligogenic Linkage Analysis Routines). ResultsSignificant heritability was found for the rates of change of 6 white matter tract microstructural properties and for change in the connectivity between the ventral attention network and both the cognitive control and dorsal attention networks. Change in hyperactivity-impulsivity was associated with heritable change in white matter tracts metrics and change in the connectivity between the ventral attention and cognitive networks. ConclusionsThe relatively small number of heritable, ADHD-associated developmental neural phenotypes can serve as phenotypes for future gene discovery and understanding.

Intrinsic and extrinsic epigenetic age acceleration are associated with hypertensive target organ damage in older African Americans

BackgroundEpigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries.MethodsWe investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996–2000), and measures of target organ damage were assessed in a follow-up visit (2000–2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated.ResultsAfter adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed.ConclusionsMeasures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.

Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes

A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. Cross-sectional study. We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines. Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (rg=-0.14; P= .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (rg ≥ 0.45; P≤ 3.0 × 10-4) and between CDR and POAG were high (rg= 0.57; P= 2.8 × 10-10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (rg range-0.18 to 0.11) and nonsignificant (P ≥ .07). These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.

Abstract P109: Genetic Correlates of Resilience Among African American Families From the Jackson Heart Study

Background: Research has reported that measures of resilience, such as optimism, social support, and religious coping are positively associated with longevity, but there are limited studies on the genetic contribution of resilience among African Americans. Utilizing Jackson Heart Study (JHS) data, we examined the heritability estimates of markers of resilience and their association with proportion of West African genetic ancestry (pAfr) in order to understand familial patterns of resilience among African Americans. Hypothesis: We hypothesized that genetic variation would contribute significantly to variation in indicators of resilience, and that pAfr will be positively associated with greater resilience in African Americans. Methods: Resilience measures (optimism, social support, social networks, religious experiences, and religious practices and coping) were obtained from validated questionnaires. Scores were created for each resilience measure and then all measures were summed to create a total resilience score among 1,200 related and 1,456 unrelated individuals of the JHS cohort. We then analyzed the subset of related individuals to estimate polygenic heritability for resilience measures using Sequential Oligogenic Linkage Analysis Routines (SOLAR), and evaluated the subset of unrelated participants for the association between resilience and pAfr using a multiple linear regression model. The pAfr was estimated from more than 1,400 ancestry informative markers that differentiate West African genetic ancestry from European ancestry using HAPMIX genetic software. In both analyses, we controlled for age, sex, age-by-sex interaction, education, physical activity, smoking and depressive symptoms. Results: In related individuals, we found a significant proportion of variation (h 2 ±SE; p-value) due to familial correlation on religious practices and coping (0.15±0.09; p=0.0371); religious experience (0.26±0.09; p&lt;0.001); social networks (0.32±0.07; p&lt;0.001); and optimism (0.21±0.08; p&lt;0.001). Heritability estimates for total resilience and social support were not significant. In the subset of unrelated individuals, we found that pAfr was significantly associated (beta±SE; p-value) with total resilience (3.08±1.44; p=0.0327), religious experience (5.16±2.55; p=0.0437), and religious practices and coping (3.77±1.23; p=0.0023) in men but not in women. Conclusion: In this sample of African Americans, we found evidence that variation in markers of resilience are influenced by genetic ancestry and sex. West African genetic background was associated with markers of resilience in men only. Due to lack of household effects we could not account for influence of the common environment, which is a limitation of these findings. However, because we found genetic influences of resilience, future studies that explore associations with longevity loci are warranted.

Heritability and familiality of psychopathologic dimensions in Korean families with schizophrenia

Categorical syndromes such as schizophrenia could be a combination of many continuous mental structure phenotypes including several personality development/degeneration dimensions. This study investigated the heritability and familiality of symptom check list (SCL) psychopathologic dimensions in Korean schizophrenia linkage disequilibrium families. We recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We used the SCL questionnaire to measure psychopathologic dimensions. The heritability of symptomatic dimensions in 543 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Psychopathologic dimensions in the 543 family members were compared with those in 307 healthy unrelated controls to measure familiality on using analysis of variance (ANOVA) analysis. Five of the nine SCL variables were significantly heritable and were included in the subsequent analyses. The three groups (control, unaffected first-degree relative, schizophrenia patient) were found to be significantly different with regard to the expected order of average group scores for all heritable dimensions. Aberrations in several symptomatic dimensions could contribute to the complexity of schizophrenia syndrome as a result of genetic-environment coaction or interaction in spite of some limitations (recruited family, phenotyping).

SA106 - HERITABILITY AND FAMILIALITY OF NEO PERSONALITY DIMENSIONS IN THE KOREAN FAMILIES WITH SCHIZOPHRENIA

Background Categorical syndrome such as schizophrenia could be the complex of many continuous mental structure phenotypes including several personality development/degeneration dimensions. Previous many models suggest that personality dimensions are heritable and influence the genetic loading of schizophrenia. The psychobiological model of personality suggests an individual's temperament is heritable and regulated by neurotransmission linked to the pathophysiology of schizophrenia. Recently, evidence has appeared that dimensions of character are also heritable and may influence the risk for schizotypy. This is the study to search heritability and familiality of personality dimensions in the Korean schizophrenic LD (Linkage Disequilibrium) families. Methods We have recruited 179 probands (with schizophrenia) with their parents and siblings whenever possible. We have used NEO questionnaires for measuring personality and symptomatic dimensions. Heritabilities of personality dimensions in total 472 family members were estimated using Sequential Oligogenic Linkage Analysis Routines(SOLAR). Personality dimensions in total family members were compared with those in 336 healthy unrelated controls for measuring the familialities using ANOVA analysis. Genetic/environmental correlations with symptomatic dimensions for significant personality dimensions aggregated in families were also investigated using SOLAR. Results Heritability: Four of the 5 NEO variables were significantly heritable and were included in the subsequent analyses. Familial aggregation: The three groups (control, unaffected 1st degree relative, case) were found to be significantly different and with the expected order of average group scores for all heritable dimensions. Low Extroversion and low Conscientiousness could differentiate the cases from the 1st degree relatives and controls qualitatively. Genetic/environmental correlation: genetic/environmental correlations with schizophrenic phenotype was suggested. Discussion Our results show that the aberrations in several personality dimensions could form the complexity of schizophrenic syndrome as a result of genetic-environment coactions or interactions in spite of some limitations (recruited family, phenotyping). Four of the five NEO variables (Extroversion, Conscientiousness, Neuroticism, Openness) were significantly heritable and were included in the subsequent analyses. Two endophenotypes (low Extroversion and low Conscientiousness) could differentiate the cases from the 1st degree relatives and controls qualitatively. The control, unaffected 1st degree relative, and case groups were significantly different and with the expected order of average group scores for two endophenotypes. (Neuroticism and Openness) Based on these results genetic and environmental correlations with schizophrenic phenotype was suggested. Finally, future genome-wide linkage and association studies with much more complete pedigrees are expected.

Heritability and Familiality of MMPI Personality Dimensions in the Korean Families with Schizophrenia.

ObjectiveCategorical syndrome such as schizophrenia could be the complex of many continuous mental structure phenotypes including several personality development/degeneration dimensions. This is the study to search heritability and familiality of MMPI personality dimensions in the Korean schizophrenic LD (Linkage Disequilibrium) families. MethodsWe have recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We have used MMPI questionnaires for measuring personality and symptomatic dimensions. Heritabilities of personality dimensions in total 543 family members were estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Personality dimensions in total family members were compared with those in 307 healthy unrelated controls for measuring the familialities using ANOVA analysis. ResultsSeven of the 10 MMPI variables were significantly heritable and were included in the subsequent analyses. The three groups (control, unaffected 1st degree relative, case) were found to be significantly different with the expected order of average group scores for all heritable dimensions. ConclusionOur results show that the aberrations in several personality dimensions could form the complexity of schizophrenic syndrome as a result of genetic-environment coactions or interactions in spite of some limitations (recruited family, phenotyping).

Genome-wide analysis in multiple-case families: assessing the relationship between triglyceride and methylation

The main goal of this paper is to estimate the effect of triglyceride levels on methylation of cytosine-phosphate-guanine (CpG) sites in multiple-case families. These families are selected because they have 2 or more cases of metabolic syndrome (primary phenotype). The methylations at the CpG sites are the secondary phenotypes. Ascertainment corrections are needed when there is an association between the primary and secondary phenotype. We will apply the newly developed secondary phenotype analysis for multiple-case family studies to identify CpG sites where methylations are influenced by triglyceride levels. Our second goal is to compare the performance of the naïve approach, which ignores the sampling of the families, SOLAR (Sequential Oligogenic Linkage Analysis Routines), which adjusts for ascertainment via probands, and the secondary phenotype approach. The analysis of possible CpG sites associated with triglyceride levels shows results consistent with the literature when using the secondary phenotype approach. Overall, the secondary phenotype approach performed well, but the comparison of the different approaches does not show significant differences between them. However, for genome-wide applications, we recommend using the secondary phenotype approach when there is an association between primary and secondary phenotypes, and to use the naïve approach otherwise.

Genome-wide linkage scan for loci influencing plasma triglyceride levels

We conducted a genome-wide linkage scan to detect loci that influence the levels of fasting triglycerides in plasma. Fasting triglyceride levels were available at 4 time points (visits), 2 pre- and 2 post-fenofibrate intervention. Multipoint identity-by-descent (MIBD) matrices were derived from genotypes using IBDLD. Variance-component linkage analyses were then conducted using SOLAR (Sequential Oligogenic Linkage Analysis Routines). We found evidence of linkage (logarithm of odds [LOD] ≥3) at 5 chromosomal regions with triglyceride levels in plasma. The highest LOD scores were observed for linkage to the estimated genetic value (additive genetic component) of the log-normalized triglyceride levels in plasma. Our results suggest that a chromosome 10 locus at 37 cM (LODpre = 3.01, LODpost = 3.72) influences fasting triglyceride levels in plasma regardless of the fenofibrate intervention, and that loci in chromosomes 1 at 170 cM and 4 at 24 cM ceases to affect the triglyceride levels when fenofibrate is present, while the regions in chromosomes 6 at 136 to 162 cM and 11 at 39 to 40 cM appear to influence triglyceride levels in response to fenofibrate.

Heritability and genetic associations of triglyceride and HDL-C levels using pedigree-based and empirical kinships

The heritability of a phenotype is an estimation of the percent of variance in that phenotype that is attributable to additive genetic factors. Heritability is optimally estimated in family-based sample populations. Traditionally, this involves use of a pedigree-based kinship coefficient generated from the collected genealogical relationships between family members. An alternative, when dense genotype data are available, is to directly measure the empirical kinship between samples. This study compares the use of pedigree and empirical kinships in the GAW20 data set. Two phenotypes were assessed: triglyceride levels and high-density lipoprotein cholesterol (HDL-C) levels pre- and postintervention with the cholesterol-reducing drug fenofibrate. Using SOLAR (Sequential Oligogenic Linkage Analysis Routines), pedigree-based kinships and empirically calculated kinships (using IBDLD and LDAK) were used to calculate phenotype heritability. In addition, a genome-wide association study was conducted using each kinship model for each phenotype to identify genetic variants significantly associated with phenotypic variation. The variant rs247617 was significantly associated with HDL-C levels both pre- and post-fenofibrate intervention. Overall, the phenotype heritabilities calculated using pedigree based kinships or either of the empirical kinships generated using IBDLD or LDAK were comparable. Phenotype heritabilities estimated from empirical kinships generated using IBDLD were closest to the pedigree-based estimations. Given that there was not an appreciable amount of unknown relatedness between the pedigrees in this data set, a large increase in heritability in using empirical kinship was not expected, and our calculations support this. Importantly, these results demonstrate that when sufficient genotypic data are available, empirical kinship estimation is a practical alternative to using pedigree-based kinships.

Heritability of muscle mass in Korean parent–offspring pairs in the Fifth Korean National Health and Nutrition Examination Survey (KNHANES V)

ObjectivesDecreased muscle mass is known to be associated with several serious medical conditions. We analyzed the Fifth Korean National Health and Nutrition Examination Survey (KNHANES V, 2010–2011) to estimate the heritability of muscle mass in Korean parent-offspring pairs. Study DesignCross-sectional. Main outcome measuresA total of 1233 parents (average age 57.67 ± 8.50 years) and 917 offspring (average age 29.10 ± 7.57 years) from 743 families were included in the analysis. Muscle mass was estimated based on three different indices: appendicular skeletal muscle mass (ASM) measured with a dual-energy X-ray absorptiometry (DXA), weight-adjusted ASM (SMI), and height-adjusted ASM (RASM). The heritability was estimated by employing the maximum-likelihood variance components implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR). The best-fitting model was determined out of four polygenic models. Pearson’s partial correlation coefficient was also calculated using the muscle mass indices to further study the association between father or mother and son or daughter pairs. ResultsThe heritability estimates of the muscle mass indices ranged from 55% to 80% (all p < 0.01). The correlation coefficient of father and offspring ranged from 0.11 to 0.40, while that of mother and offspring ranged from 0.23 to 0.43 (all p < 0.01). ConclusionsThe heritability estimates of muscle mass in Koreans are large and significant, suggesting that parental muscle mass is an important predictor of the offspring’s muscle mass. The result implies that there may be a genetic factor partly determining muscle mass.

Transmissibility and familiality of NEO personality dimensions in a sample of Korean families with schizophrenia.

Categorical syndromes such as schizophrenia may represent complexes of many continuous psychological structural phenotypes along several dimensions of personality development/degeneration. The present study investigated the heritability and familiality of Neuroticism-Extraversion-Openness to experience (NEO) personality dimensions in Korean families with schizophrenic linkage disequilibrium (LD).We have recruited 204 probands (with schizophrenia) with their parents and siblings whenever possible. We have used NEO questionnaires for measuring personality and symptomatic dimensions. Heritabilities of personality dimensions in total 543 family members were estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Personality dimensions in total family members were compared with those in 307 healthy unrelated controls for measuring the familialities using ANOVA analysis.Four of the 5 NEO variables were significantly heritable and were included in the subsequent analyses. The 3 groups (control, unaffected first-degree relative, case) were found to be significantly different and with the expected order of average group scores for all heritable dimensions.Our results show that the aberrations in several personality dimensions could form the complexity of schizophrenic syndrome as a result of genetic–environment coactions or interactions in spite of some limitations (recruited family, phenotyping).

Familial resemblance in trabecular and cortical volumetric bone mineral density and bone microarchitecture as measured by HRpQCT.

To estimate the heritability of bone geometry, volumetric bone mineral density (vBMD) and microarchitecture of trabecular (Tb) and cortical (Ct) bone measured by high resolution peripheral quantitative computerised tomography (HRpQCT) at the distal radius and tibia and to investigate the genetic correlations of these measures. Participants were 177 mother-offspring pairs from 162 families (mothers, mean age (SD) = 52.1 (4.7) years; offspring, 25.6 (0.73) years). Trabecular and cortical bone measures were obtained by HRpQCT. Multivariable linear regression was used to analyse the association of bone measures between mother and offspring. Sequential Oligogenic Linkage Analysis Routines (SOLAR) software was utilised to conduct quantitative genetic analyses. All maternal bone measures were independently associated with the corresponding bone measures in the offspring before and after adjustment for age, sex, weight and height. Heritability estimates ranged from 24% to 67% at the radius and from 42% to 74% at the tibia. The relationship for most bone geometry measures was significantly stronger in mother-son pairs (n = 107) compared with mother-daughter pairs (n = 70) (p < 0.05). In contrast, the heritability for most vBMD and microarchitecture measures were higher in mother-daughter pairs. Bivariate analyses found moderate to strong genetic correlations across all measures between radius and tibia (Rg = 0.49 to 0.93). Genetic factors have an important role in the development of bone geometry, vBMD and microarchitecture. These factors are strongly shared for the radius and tibia but vary by sex implying a role for imprinting.