A 2-step penalized regression method for family-based next-generation sequencing association studies

Large-scale genetic studies are often composed of related participants, and utilizing familial relationships can be cumbersome and computationally challenging. We present an approach to efficiently handle sequencing data from complex pedigrees that incorporates information from rare variants as well as common variants. Our method employs a 2-step procedure that sequentially regresses out correlation from familial relatedness and then uses the resulting phenotypic residuals in a penalized regression framework to test for associations with variants within genetic units. The operating characteristics of this approach are detailed using simulation data based on a large, multigenerational cohort

Ethnic differences and heritability of blood pressure circadian rhythm in African and European American youth and young adults

Background: The aim of this study was to investigate whether blood pressure (BP) circadian rhythm in African Americans differed from that in European Americans. We further examined the genetic and/or environmental sources of variances of the BP circadian rhythm parameters and the extent to which they depend on ethnicity or sex. Method: Quantification of BP circadian rhythm was obtained using Fourier transformation from the ambulatory BP monitoring data of 760 individuals (mean age, 17.2 +/- 3.3; 322 twin pairs and 116 singletons; 351 African Americans). Results: BP circadian rhythm showed a clear difference by ethnic group with African Americans having a lower amplitude (P = 1.5e-08), a lower percentage rhythm (P = 2.8e-11), a higher MESOR (P = 2.5e-05) and being more likely not to display circadian rhythm (P = 0.002) or not in phase (P = 0.003). Familial aggregation was identified for amplitude, percentage rhythm and acrophase with genetic factors and common environmental factors together accounting for 23 to 33% of the total variance of these BP circadian rhythm parameters. Unique environmental factors were the largest contributor explaining up to 67--77% of the total variance of these parameters. No sex or ethnicity difference in the variance components of BP circadian rhythm was observed. Conclusion: This study suggests that ethnic differences in BP circadian rhythm already exist in youth with African Americans having a dampened circadian rhythm and better BP circadian rhythm may be achieved by changes in environmental factors

Decreased heritability and emergence of novel genetic effects on pulse wave velocity from youth to young adulthood

Increased arterial stiffness measured by pulse wave velocity (PWV) is an important parameter in the assessment of cardiovascular risk. Our previous longitudinal study has demonstrated that carotid-distal PWV showed reasonable stability throughout youth and young adulthood. This stability might be driven by genetic factors that are expressed consistently over time. We aimed to illustrate the relative contributions of genetic and environmental factors to the stability of carotid-distal PWV from youth to young adulthood. We also examined potential ethnic differences. For this purpose, carotid-distal PWV was measured twice in 497 European American (EA) and African American (AA) twins, with an average interval time of 3 years. Twin modelling on PWV showed that heritability decreased over time (62-35%), with the nonshared environmental influences becoming larger. There was no correlation between the nonshared environmental factors on PWV measured at visit 1 and visit 2, with the phenotypic tracking correlation (r=0.32) completely explained by shared genetic factors over time. Novel genetic influences were identified accounting for a significant part of the variance (19%) at the second measurement occasion. There was no evidence for ethnic differences. In summary, novel genetic effects appear during development into young adulthood and account for a considerable part of the variation in PWV. Environmental influences become larger with age for PWV

Genetic and Environmental Influences on Blood Pressure and Body Mass Index in the National Academy of Sciences-National Research Council World War II Veteran Twin Registry

Blood pressure (BP) and obesity phenotypes may covary due to shared genetic or environmental factors or both. Furthermore, it is possible that the heritability of BP differs according to obesity status-a form of GxE interaction. This hypothesis has never been tested in White twins. The present study included 15 924 White male twin pairs aged between 15 and 33 years from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry. Systolic and diastolic BPs, as well as height and weight, were measured at the induction physical examination. Body mass index (BMI) was used as the index of general obesity. Quantitative genetic modeling was performed using Mx software. Univariate analysis showed that narrow sense heritabilities (95% CI) for systolic BP, diastolic BP, height, and BMI were 0.401 (0.381-0.420), 0.297 (0.280-0.320), 0.866 (0.836-0.897), and 0.639 (0.614-0.664), respectively. Positive phenotypic correlations of BMI with systolic BP (r=0.13) and diastolic BP (r=0.08) were largely due to genetic factors (70% and 86%, respectively). The gene-BMI interaction analysis did not show any support for a modifying effect of BMI on genetic and environmental influences of systolic BP and diastolic BP. Our results suggest that correlations between BP and BMI are mainly explained by common genes influencing both. Higher BMI levels have no influence on the penetrance of genetic vulnerability to elevated BP. These conclusions may prove valuable for gene-finding studies

Linkage and linkage disequilibrium analysis of the lipoprotein lipase gene with lipid profiles in Chinese hypertensive families

A B S T R A C T Elevated TG [triacylglycerol (triglyceride)] is a significant independent risk factor for cardiovascular disease. LPL (lipoprotein lipase) is one of the key enzymes in the metabolism of the TG-rich lipoproteins which hydrolyses TG from the chylomicrons and very-LDL (low-density lipoprotein). To investigate the relationship between the LPL gene and lipid profiles, especially TG, in 148 hypertensive families, we have chosen seven flanking microsatellite markers and four internal markers of the LPL gene and conducted linkage analysis by SOLAR and S.A.G.E. (statistical analysis for genetic epidemiology)/SIBPAL 2 programs, and linkage disequilibrium analysis by QTDT (quantitative transmission/disequilibrium test) and GOLD (graphical overview of linkage disequilibrium). There were statistically significant differences in lipid levels between subjects without and with hypertension within families. A maximum LOD score of 1.3 with TG at the marker D8S261 was observed by SOLAR. Using S.A.G.E./SIBPAL 2, we identified a linkage with TG at the marker 'ATTT' located within intron 6 of the LPL gene (P = 0.0095). Two SNPs (single nucleotide polymorphisms), HindIII and HinfI, were found in linkage disequilibrium with LDLcholesterol levels (P = 0.0178 and P = 0.0088 respectively). A strong linkage disequilibrium was observed between the HindIII in intron 8 and HinfI in the exon 9 (P < 0.00001, D = 0.895). Linkage disequilibrium was also found between the 'ATTT' polymorphism in intron 6 and two SNPs (P = 0.0021 and D = 0.611 for HindIII; and P = 0.00004, D = 0.459 for HinfI). The present study in the Chinese families with hypertension suggested that the LPL gene might influence lipid levels, especially TG metabolism. Replication studies both in Chinese and other populations are warranted to confirm these results

Genetic and Environmental Effects on Gene Expression Signatures of Blood Pressure A Transcriptome-Wide Twin Study

Recently, 2 transcriptome-wide studies identified 40 genes that were differentially expressed in relation to blood pressure. However, to what extent these BP-related gene expression signatures and their associations with BP are driven by genetic or environmental factors has not been investigated. In this study of 391 twins (193 twin pairs and 5 singletons; age 55-69 years; 40% male; 57% monozygous) recruited from the Finnish Twin Cohort, transcriptome-wide data on peripheral leukocytes were obtained using the Illumina HT12 V4 array. Our transcriptome-wide analysis identified 1 gene (MOK [MAPK/MAK/MRK overlapping kinase], P=7.16x10(-8)) with its expression levels associated with systolic BP at the cutoff of false-discovery rate</p

A Genome-Wide Methylation Study of Severe Vitamin D Deficiency in African American Adolescents

To test the hypothesis that changes in DNA methylation are involved in vitamin D deficiency–related immune cell regulation using an unbiased genome-wide approach combined with a genomic and epigenomic integrative approach

Common Genes Contribute to Depressive Symptoms and Heart Rate Variability:The Twins Heart Study

Depression and reduced heart rate variability (HRV) are predictors of coronary artery disease (CAD), and highly correlated with each other. However, little is known to what extend this correlation can be explained by common genetic components. We examined 198 middle-aged male twins (121 monozygotic and 77 dizygotic) from the Vietnam Era Twin Registry. Current depressive symptoms were assessed using the Beck Depression Inventory-II and HRV was assessed on 24-hour electrocardiographic Holter recordings. Five frequency domain variables were used, including ultra low frequency (ULF), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TPow). Structural equation modeling was used to estimate shared genetic effects for depressive symptoms and the HRV frequency domains. Both depressive symptoms (h(2)=.5) and all measurements of HRV showed high heritability (h(2)=.43-.63). A significant inverse correlation was found between depressive symptoms and all HRV indices except LF and HF, with the highest coefficient (r) for TPow (r = -.24, P = .01) and ULF (r = -.24, P = .01). Bivariate genetic modeling revealed significant genetic correlations between depressive symptoms and TPow (r(A) = -.21, P = .04), as well as ULF (r(A) = -.23, P = .02). Of the total covariance between depressive symptoms and these two HRV indices, over 80% was due to the same genetic factors. In conclusion, depressive symptoms are associated with decreased HRV and this association is due, in large part, to a shared genetic effect. These results suggest that a common neurobiological dysfunction links depression and autonomic dysregulation