Variance Component Method Research Articles

A scalable and robust variance components method reveals insights into the architecture of gene-environment interactions underlying complex traits

Understanding the contribution of gene-environment interactions (GxE) to complex trait variation can provide insights into disease mechanisms, explain sources of heritability, and improve genetic risk prediction. While large biobanks with genetic and deep phenotypic data hold promise for obtaining novel insights into GxE, our understanding of GxE architecture in complex traits remains limited. We introduce a method to estimate the proportion of trait variance explained by GxE (GxE heritability) and additive genetic effects (additive heritability) across the genome and within specific genomic annotations. We show that our method is accurate in simulations and computationally efficient for biobank-scale datasets. We applied our method to common array SNPs (MAF ≥1%), fifty quantitative traits, and four environmental variables (smoking, sex, age, and statin usage) in unrelated white British individuals in the UK Biobank. We found 68 trait-E pairs with significant genome-wide GxE heritability (p<0.05/200) with a ratio of GxE to additive heritability of ≈6.8% on average. Analyzing ≈8 million imputed SNPs (MAF ≥0.1%), we documented an approximate 28% increase in genome-wide GxE heritability compared to array SNPs. We partitioned GxE heritability across minor allele frequency (MAF) and local linkage disequilibrium (LD) values, revealing that, like additive allelic effects, GxE allelic effects tend to increase with decreasing MAF and LD. Analyzing GxE heritability near genes highly expressed in specific tissues, we find significant brain-specific enrichment for body mass index (BMI) and basal metabolic rate in the context of smoking and adipose-specific enrichment for waist-hip ratio (WHR) in the context of sex.

Familial Correlation and Heritability of Hand Grip Strength in Korean Adults (Korea National Health and Nutrition Examination Survey 2014 to 2019).

The onset and progression of sarcopenia are highly variable among individuals owing to genetic and environmental factors. However, there are a limited number of studies measuring the heritability of muscle strength in large numbers of parent-adult offspring pairs. We aimed to investigate the familial correlation and heritability of hand grip strength (HGS) among Korean adults. This family-based cohort study on data from the Korea National Health and Nutrition Examination Survey (2014 to 2019) included 5,004 Koreans aged ≥19 years from 1,527 families. HGS was measured using a digital grip strength dynamometer. Familial correlations of HGS were calculated in different pairs of relatives. Variance component methods were used to estimate heritability. The heritability estimate of HGS among Korean adults was 0.154 (standard error, 0.066). Correlation coefficient estimates for HGS between parent-offspring, sibling, and spouse pairs were significant at 0.07, 0.10, and 0.23 (P<0.001, P=0.041, and P<0.001, respectively). The total variance in the HGS phenotype was explained by additive genetic (15.4%), shared environmental (11.0%), and unique environmental (73.6%) influences. The odds of weak HGS significantly increased in the offspring of parents with weak HGS (odds ratio [OR], 1.69-3.10; P=0.027-0.038), especially in daughters (OR, 2.04-4.64; P=0.029-0.034). HGS exhibits a familial correlation and significant heritable tendency in Korean adults. Therefore, Asian adults, especially women, who have parents with weak HGS, need to pay special attention to their muscle health with the help of healthy environmental stimuli.

Association of rare RNF213 variants and intracranial aneurysm risk in a Chinese population.

Genetic factors play important roles in the development of intracranial aneurysm (IA). Rare RNF213 variants have been identified as being susceptible to Moyamoya disease (MMD), non-MMD intracranial artery stenosis/occlusion disease, and other vascular disorders. This study aimed to investigate the association between rare RNF213 variants and the risk of IA in a Chinese population. We recruited 174 patients with IA for RNF213 target exome sequencing. Information on the control subjects was obtained from the 1,000 Genome Project and GeneSky in-house database. After prioritizing rare RNF213 variants, the filtered variants were confirmed by Sanger sequencing. Gene-based association analyses were performed to identify the association between variants and the disease using burden and variance component methods; that is, the weighted-sum statistic (WSS) and the sequence kernel association test (SKAT), respectively. The Student's t-test, Chi-squared test, and Fisher's exact test were used to compare the clinical characteristics between carriers and non-carriers of the RNF213 variants. After filtering, there were 14 RNF213 variants in 18 patients with IA, which were significantly associated with the disease after the gene-based association tests [minor allele frequency (MAF) <0.01, WSS P value 5.08×10-9; SKAT P value 2.96×10-6; SKAT-O P value 3.56×10-8]. Significant difference was not obtained between the carriers and non-carriers of the RNF213 variants in terms of the clinical characteristics. Rare RNF213 variants were associated with sporadic IA in a Chinese population. Our findings suggest that these rare RNF213 variants might have potentially important roles in IA. However, more comprehensive studies need to be conducted to confirm this association and causality.

ODP089 Familial correlation and heritability of muscle strength in Korean adults (KNHANES 2014-2019)

Abstract Objective The onset and progression of sarcopenia are highly variable between individuals due to genetic and environmental factors. However, studies that have measured muscle strength directly in large numbers of matched parent-adult offspring pairs are limited. In this study, we investigated familial correlation and heritability of handgrip strength (HGS) in Korean adults. Methods This was a family-based cohort study from the Korea National Health and Nutrition Examination Survey (2014-2019) including 5,004 Koreans aged ≥19 years from 1,527 families. HGS was measured using a digital grip strength dynamometer. Familial correlations for HGS were calculated in different types of relative pairs. Variance component methods were used to obtain heritability estimates. Results Mean HGS of parents were 39.3 ± 7.5 kg in fathers and 24.4 ± 5. 0 kg in mothers and those of offspring were 41.8 ± 8. 0 kg in sons and 24. 0 ± 4.8 kg in daughters. Correlation coefficient estimates between parent-offspring pairs, sibling pairs, and spouse pairs for HGS were significant as 0. 07, 0.10, and 0.23 (p &amp;lt;0. 001, p = 0. 041, and p &amp;lt;0. 001), respectively. The total variance of the phenotype under study was explained by additive genetic (15.4%), common shared environmental (11. 0%), and unique environmental (73.6%) influences. The risk of low HGS conferred by parents’ low HGS were found to be significant for individuals whose parents had low HGS (OR 3.10, 95%CI 1.14-8.45). Conclusion Muscle strength showed a familial correlation in Korean adults. A significant heritable tendency of muscle strength from parents to their adult offspring and common shared environmental influence can explain this correlation. Presentation: No date and time listed

Image-based morphometric analysis reveals moderate to highly heritable nut shape traits in pecan

Nut shape is an important trait in determining the value of a pecan (Carya illinoensis) nut crop. Nut shape influences attractiveness to consumers, nut filling, ease of mechanical cracking, and is distinctive enough that it is the primary means of cultivar identification. Narrow sense heritability (h2) of a trait is the fraction of phenotypic variance attributed to variation in genes with additive effect. Estimation of h2 is key to breeding programs as it determines the method of selection and amount of genetic gain in each breeding cycle. In the present study, we estimated the heritability of pecan nut shape characters following two different approaches. First, image-based phenotypes of pecan nuts from 34 full-sib families generated from random crosses between 31 different parents were generated and analyzed for 10 different morphometric traits using the computer program Tomato Analyzer. The narrow-sense heritability for each trait was estimated using the mid-parent offspring regression method. Second, a separate set of 19 pecan genotypes were phenotyped for the same shape traits for two years and heritabilities were estimated by variance component analysis. Heritability estimates ranged from 0.41 to 0.83 for the mid-parent offspring regression method and from 0.26 to 0.78 for variance component method. Additionally, elliptical Fourier transform was performed to study the overall variation in nut shape. The first three principal components obtained from Elliptical Fourier transform explained 65.9% of the total variation in shape attributed to the nut’s roundness and angularity of proximal and distal ends. The use of the image-based high-throughput method of phenotyping and the heritability estimates obtained in this study directly benefit pecan breeding programs focusing on nut shape traits.

Increased genetic contribution to wellbeing during the COVID-19 pandemic.

Physical and mental health are determined by an interplay between nature, for example genetics, and nurture, which encompasses experiences and exposures that can be short or long-lasting. The COVID-19 pandemic represents a unique situation in which whole communities were suddenly and simultaneously exposed to both the virus and the societal changes required to combat the virus. We studied 27,537 population-based biobank participants for whom we have genetic data and extensive longitudinal data collected via 19 questionnaires over 10 months, starting in March 2020. This allowed us to explore the interaction between genetics and the impact of the COVID-19 pandemic on individuals' wellbeing over time. We observe that genetics affected many aspects of wellbeing, but also that its impact on several phenotypes changed over time. Over the course of the pandemic, we observed that the genetic predisposition to life satisfaction had an increasing influence on perceived quality of life. We also estimated heritability and the proportion of variance explained by shared environment using variance components methods based on pedigree information and household composition. The results suggest that people's genetic constitution manifested more prominently over time, potentially due to social isolation driven by strict COVID-19 containment measures. Overall, our findings demonstrate that the relative contribution of genetic variation to complex phenotypes is dynamic rather than static.

VARIATION AMONG AGRONOMIC TRAITS AND MINERAL CONTENTS IN 15 ACCESSIONS OF GARDEN EGG PLANT (Solanum aethiopicum) IN SOUTHWEST OF NIGERIA

Throughout Africa, S. aethiopicum is very popular and plays a vital role in many human diets. Despite the fact that there are previous reports on yield characteristics and nutrition of the crop, there is a need to assess the crop for variations in mineral properties. This study aimed at determining the amount of genetic variability and level of heritability of agronomic and mineral contents of S. aethiopicum accessions. Fifteen accessions of S.aethiopicum were evaluated in an RBCD experimental design to generate data for use. Data were collected for agronomic, morphological and mineral contents. Data collected were subjected to ANOVA and the significant means were also separated using Duncan Multiple Range Test (DMRT) at 5% probability level. Variance component method was used to estimate phenotypic and genotypic variations as well as heritability. Significant differences were observed among accessions for the various morphological and mineral nutritional traits evaluated. High heritability estimates, Phenotypic and Genotypic variances were observed for mineral content and fruit yield. Genotypic and phenotypic variances ranged between 0.31 and 11078.85 for the agronomic traits. The hierarchical cluster analyses revealed five distinct clusters at similarity index of 85%. The first cluster included 6 accessions; the second included accessions NHS 101A, and OG 03; the third were NHS 104 and OG 01; the fourth included NHS 105; and the fifth included NHS 106, NHS 108, OS 02 and OS 03. Accessions OS 01 and OS 03 appear unique based on the traits for which the accessions were assessed.This study revealed that substantial variation exists within the accessions of S.aethiopicum evaluated, hence, it will help in breeding process of good quality genotypes for higher yields and mineral content.&#x0D;

Genetic association of anthropometric traits with type 2 diabetes in ethnically endogamous Sindhi families.

BackgroundEthnically endogamous populations can shed light on the genetics of type 2 diabetes. Such studies are lacking in India. We conducted this study to determine the genetic and environmental contributions of anthropometric traits to type 2 diabetes risk in the Sindhi families in central India.MethodsWe conducted a family study in Indian Sindhi families with at least one case of type 2 diabetes. Variance components methods were used to quantify the genetic association of 18 anthropometric traits with eight type 2 diabetes related traits. Univariate and bivariate polygenic models were used to determine the heritability, genetic and environmental correlation of anthropometric traits with type 2 diabetes related traits.ResultsWe included 1,152 individuals from 112 phenotyped families. The ascertainment-bias corrected prevalence of type 2 diabetes was 35%. Waist circumference, hip circumference and the biceps, triceps, subscapular and medial calf skinfold thicknesses were polygenically and significantly associated with type 2 diabetes. The range of heritability of the anthropometric traits and type 2 diabetes related traits was 0.27–0.73 and 0.00–0.39, respectively. Heritability of type 2 diabetes as a discrete trait was 0.35. Heritability curves demonstrated a substantial local influence of type 2 diabetes related traits. Bivariate trait analyses showed that biceps and abdominal skinfold thickness and all waist-containing indexes were strongly genetically correlated with type 2 diabetes.ConclusionsIn this first study of Sindhi families, we found evidence for genetic and environmental concordance of anthropometric traits with type 2 diabetes. Future studies need to probe into the genetics of type 2 diabetes in this population.

Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia

BackgroundLatency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. MethodsSchizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. Results980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34–41% for latency and 45–59% for magnitude. ConclusionBoth startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

Heritability and the Genetic Correlation of Heart Rate Variability and Blood Pressure in >29 000 Families: The Lifelines Cohort Study.

Dysregulation of the cardiac autonomic nervous system, as indexed by reduced heart rate variability (HRV), has been associated with the development of high blood pressure (BP). However, the underlying pathological mechanisms are not yet fully understood. This study aimed to estimate heritability of HRV and BP and to determine their genetic overlap. We used baseline data of the 3-generation Lifelines population-based cohort study (n=149 067; mean age, 44.5). In-house software was used to calculate root mean square of successive differences and SD of normal-to-normal intervals as indices of HRV based on 10-second resting ECGs. BP was recorded with an automatic BP monitor. We estimated heritabilities and genetic correlations with variance components methods in ASReml software. We additionally estimated genetic correlations with bivariate linkage disequilibrium score regression using publicly available genome-wide association study data. The heritability (SE) estimates were 15.6% (0.90%) for SD of normal-to-normal intervals and 17.9% (0.90%) for root mean square of successive differences. For BP measures, they ranged from 24.4% (0.90%) for pulse pressure to 30.3% (0.90%) for diastolic BP. Significant negative genetic correlations (all P<0.0001) of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (-0.20/-0.16) and with diastolic BP (-0.15/-0.13) were observed. LD score regression showed largely consistent genetic correlation estimates of root mean square of successive differences/SD of normal-to-normal intervals with systolic BP (range, -0.08 to -0.23) and diastolic BP (range, -0.20 to -0.27). Our study shows a substantial contribution of genetic factors in explaining the variance of HRV and BP measures in the general population. The significant negative genetic correlations between HRV and BP indicate that genetic pathways for HRV and BP partially overlap.

Estimating variances in time series kriging using convex optimization and empirical BLUPs

We propose a two-stage estimation method of variance components in time series models known as FDSLRMs, whose observations can be described by a linear mixed model (LMM). We based estimating variances, fundamental quantities in a time series forecasting approach called kriging, on the empirical (plug-in) best linear unbiased predictions of unobservable random components in FDSLRM. The method, providing invariant non-negative quadratic estimators, can be used for any absolutely continuous probability distribution of time series data. As a result of applying the convex optimization and the LMM methodology, we resolved two problems $-$ theoretical existence and equivalence between least squares estimators, non-negative (M)DOOLSE, and maximum likelihood estimators, (RE)MLE, as possible starting points of our method and a practical lack of computational implementation for FDSLRM. As for computing (RE)MLE in the case of $ n $ observed time series values, we also discovered a new algorithm of order $\mathcal{O}(n)$, which at the default precision is $10^7$ times more accurate and $n^2$ times faster than the best current Python(or R)-based computational packages, namely CVXPY, CVXR, nlme, sommer and mixed. We illustrate our results on three real data sets $-$ electricity consumption, tourism and cyber security $-$ which are easily available, reproducible, sharable and modifiable in the form of interactive Jupyter notebooks.

English

Drought is the most important abiotic limitation to groundnut yields across the world, and the Northern Regions of Ghana. The study estimated the heritability and genetic variability of selected parents of groundnut for drought tolerance traits to aid in their effective selection and utilization. The North Carolina II mating design was adopted while the variance component method was used to estimate heritabilities in the narrow and broad sense as well. Chlorophyll content (greenness of leaves) was recorded at 60 and 80 DAP. The objective was to measure the chlorophyll content and hence the drought tolerance performance of the entries. Mean squares caused by differences among crosses was partitioned into difference due to male parents and female parents, which was attributed to general combining ability (GCA), as well as difference due to male x female interaction, which was attributed to specific combining ability (SCA). Narrow Sense Heritability from the variance components for different traits varied under both water regimes, ranging from 12.2% to 95.7%. The most heritable traits were: dry biomass weight (95.7%), days to 50% flowering (91.0%), seed yield (90.0%), plant height at harvest (76.0%), SCMR 60 DAP (71.7%), days to maturity (67.0%) and SCMR 80 DAP (66.0%). Pod yield (12.3%) and harvest index (12.2%) exhibited low narrow sense heritabilities. Additive gene effects largely controlled the inheritance of pod, seed and biomass yields. Positive association between most yield and yield components as well as higher heritabilities shows that selection for higher yield and maturity is conceivable in improving groundnuts. Key words: Abiotic, constraints, chlorophyll content, drought, genetic, groundnut, heritability, North Carolina II mating design, tolerance, yield.

Clinical and genetic validity of quantitative bipolarity

Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h2 = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h2 = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.

1717-P: Burden of Type 2 Diabetes and Its Genetic Determinants in Indian Populations: Findings from the INDIGENIUS Consortium

To address the public health issue of type 2 diabetes (T2D) and its genetic profile in India, we aimed to evaluate genetic determinants of T2D using family-based cohorts from four distinct Endogamous Ethnic Groups (EEGs) representing two Northern (Punjab [Sikhs: SI] and Rajasthan [Agarwals: AG]) and two Southern (Tamil Nadu [Chettiars: CH] and Andhra Pradesh [Reddys: RE]) states of India, and to examine whether genetic variants found through targeted sequencing of the previously established 8 South Asian T2D risk loci (including the one from the Sikh population) are relevant to the AG, CH, and RE EEGs. In this study, we report the findings of T2D occurrence and genetic basis of T2D/related traits from the EEGs, as part of the INDIGENIUS (Indian Diabetes Genetic Studies in collaboration with U.S.) consortium studies, supported by an Indo-U.S. Collaborative Research Partnership on T2D. Data and samples were collected from three EEGs: AG (N=530, Families=25, mean age=43y, mean BMI=27, T2D=37%); CH (N=518, families=21, Age=47y, BMI=27, T2D=33%), and RE (N=500, Families=22, Age=46y, BMI=27, T2D=36%). Each of the families from an EEG was ascertained by a proband with T2D. The status of T2D was defined by ADA 2018 guidelines (fasting glucose≥126 mg/dl or HbA1c≥6.5% and/or use of diabetes medication/history). Similar characteristics for the SI EEG (N=1260, Families=324, Age=51y, BMI=27, T2D=75%) were obtained previously. We used the variance components method as implemented in the program SOLAR to carry out genetic analyses. All analyses were adjusted for age and sex effects. In all cohorts, T2D heritability (h2) (p&amp;lt;0.05) ranged from 30% (CH) to 81% (AG). Other T2D-related traits (e.g., BMI, lipids, blood pressure, insulin, glucose) in AG, CH, and RE EEGs exhibited strong genetic influences (h2 range: 15% [triglycerides] - 90% [glucose; non-T2D]). Our findings highlight high burden of T2D in Indian EEGs with significant additive genetic influences on T2D and its related traits. Disclosure V. Venkatesan: None. J.C. Lopez-Alvarenga: None. R. Arya: None. T. Koshy: None. U. Ravichandran: None. S. Sharma: None. S. Lodha: None. A.R. Ponnala: None. K.K. Sharma: None. M.V. Shaik: None. R.G. Resendez: None. D. Ramu: None. P. Venugopal: None. P. R.: None. N. S.: None. J.A. Ezeilo: None. C.A. Bejar: None. S. Mummidi: None. C. Natesan: None. J. Blangero: None. K.M. Medicherla: None. S. Thanikachalam: None. T. Sadras Panchatcharam: None. D. K.: None. R. Gupta: None. D.K. Sanghera: None. R. Duggirala: None. S.F. Paul: None. Funding Indian Council of Medical Research (55/6/2/Indo-US/2014-NCD-II); National Institute of Diabetes and Digestive and Kidney Diseases (R21DK105913)

SU7 - BEYOND THE TRANSLOCATION: WHOLE GENOME SEQUENCING ANALYSIS OF THE SCOTTISH T(1;11) FAMILY

Background Psychiatric illnesses are a group of genetically-related disorders with highly polygenic architecture and a significant environmental component. Even within families, these conditions show the attributes of many complex traits: reduced penetrance and phenotypic heterogeneity. An extended pedigree design has several advantages: it avoids population stratification and reduces genetic heterogeneity, narrowing the search for rare and functional variants that segregate with a phenotype. We have analysed a multigenerational pedigree where major mental illness segregates with a balanced translocation between chromosomes 1 and 11. Methods Whole genome sequencing was performed on 49 family members (20 carriers, 29 non-carriers of the translocation). Polygenic risk scores were calculated using summary statistics from the PGC MDD 2011 and used to predict diagnosis. Multipoint linkage analyses were performed using the variance components method implemented in SOLAR. Multiple phenotypic classes were used constructed to reflect the multiple phenotypes within the family. Fine-mapping was performed using two-point linkage analyses across the linked regions and association analyses performed in a Scottish cohort with measures of mental health, cognitive and personality traits (N= 6,555; 2,060 cases and 4,495 controls). Results Two genome-wide significant peaks with LOD > 5.5 were detected on the translocated chromosomes 1 and 11 with maximum linkage to schizophrenia, bipolar disorder, recurrent major depression and cyclothymia; as previously noted for the translocation itself. In addition, two further peaks, a second on chromosome 1 and a peak on chromosome 5, showed genome-wide significant linkage to affective disorder (bipolar disorder, and major depressive disorder). Polygenic risk scores of schizophrenia and bipolar disorder, but not major depressive disorder significantly predict mental illness in the family. Functional annotation of the whole genome sequence, and case-control association for affective disorder in the Scottish population, support a role for GRM5, CNTN5 and PDE4D in the phenotypic heterogeneity seen in the family. Discussion These results suggest that the high density of psychiatric illness in the t(1;11) family may be a combination of: direct effects of the translocation on the genes located at the breakpoint (DISC1, DISC2, DISC1FP), “locking together” of additional familial risk factors and the accumulation of common risk variants. We have identified additional modifying loci that may explain the variance in disease expression. Our findings suggest that pleiotropy may play a significant role and that this is now tractable by whole genome sequencing in families.

Familial resemblances in human plasma metabolites are attributable to both genetic and common environmental effects

Metabolites are of great importance for understanding the pathogenesis of several diseases. Understanding the genetic contribution to metabolite concentrations may provide insights into mechanisms of complex diseases. Several studies have investigated heritability of metabolites but none investigated potential influences of genetic and environmental factors on the relationship between metabolites and cardiometabolic (CM) risk factors. Thus, we tested the hypothesis that both genetic and common environmental effects contribute to the variance of plasma metabolite concentrations and that shared genetic and environmental effects explain their phenotypic correlations with CM risk factors. To test this hypothesis, variance component method and bivariate genetic analysis were performed in a family-based sample of 48 French Canadians from 16 families. Familial resemblances were computed for all 147 detected metabolites and 9 (acetylornithine, acylcarnitine C9, arginine, phosphatidylcholine acyl-alkyl C36:4, serotonin, lysophosphatidylcholine acyl C20:4, citrulline, asymmetric dimethylarginine, phosphatidylcholine acyl-alkyl C36:5) showed a significant familial effect (55.7%, 18.7%, and 37.0% for maximal heritability, genetic heritability, and common environmental effect, respectively). Citrulline, phosphatidylcholine acyl-alkyl C36:4, phosphatidylcholine acyl-alkyl C36:5, and serotonin had significant phenotypic correlations with CM risk factors. Citrulline had a positive genetic correlation with apolipoprotein B100, while phosphatidylcholine acyl-alkyl C36:5 had a positive environmental correlation with total cholesterol. In conclusion, familial resemblances in metabolite concentrations were mainly attributable to common environmental effect when considering metabolites with a significant familial effect. Common genetic and environmental factors may also influence the relationship between metabolites and CM risk factors.

Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort.

Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users. We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined. Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P<10-300) which remained significant after adjusting for prespecified covariates (adjusted β, -5.59; SE, 0.12; P<10-300). Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least 1 first-degree relative who was also a statin user (n=1036), heritability of statin LDL-C response was estimated at 11.7% (SE, 8.6%; P=0.087). Using electronic health record data, we observed a statin LDL-C dose-response consistent with the rule of 6% from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of electronic health records as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.

Familial clustering of vitamin D deficiency via shared environment: The Korean National Health and Nutrition Examination Survey 2008–2012

Familial correlation of serum 25-hydroxyvitamin D concentration (25(OH)D) was reported in twin- or parent-offspring studies. However, data on relative contribution of environmental factors on familial clustering of 25(OH)D in extended families are limited. We performed cross-sectional study using data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2012. Familial correlations of 25(OH)D were estimated in 28,551 subjects from 10,882 families. The variance component method was used to assess the relative contribution of additive genetic or environmental contributions to the variation in 25(OH)D level. Logistic regression models with interaction term were built to evaluate the differential influence of parental vitamin D status on the adolescents and adults offspring. Mean serum 25(OH)D concentration of subjects was 44.6 nmol/L (vitamin D insufficiency (30-50 nmol/L), 51%; vitamin D deficiency ( < 30 nmol/L), 17%). Familial clustering explained 40% of the total variation in 25(OH)D. In the variance component model, 4%, 39%, and 57% of the variation in serum 25(OH)D level was attributed to additive genetic, common shared environmental, and individual environmental factors, respectively. The odds of vitamin D deficiency in offspring with both parents with vitamin D deficiency compared with those with both parents with sufficient vitamin D levels was greater in adolescents ( < 19 years) than in adults ( ≥ 19 years) (odds ratio = 41.1 vs. 12.5; p for interaction = 0.03). We found a familial clustering of vitamin D deficiency in a large family-based cohort. Parental influence on vitamin D status of offspring was greater in adolescents than in adults.

Abstract P050: Correlates of Serum Cortisol and its Prognostic Value in the Community

Introduction: Community-based data on correlates of serum cortisol are scarce. We investigated the sources of variability in morning serum cortisol, and its relation to cardiometabolic outcomes in a large biracial sample. Hypothesis: Serum cortisol is monotonically associated with cardiometabolic outcomes, an effect that is potentiated by aldosterone. Methods: We included 2896 whites (Framingham Heart Study [Generation 3], 53% women, mean age 44 years) and 2479 blacks (Jackson Heart Study, 52% women, mean age 53 years). Cohort-and sex-specific linear regression was used to identify cortisol correlates. Heritability was derived using the variance-components method. Cohort- and sex-specific logistic regression was used to relate cortisol to progression in blood pressure (BP) or fasting blood glucose (FBG) categories, and incidence of hypertension (HTN), diabetes (DM) or metabolic syndrome (MetS). Results: Serum cortisol was higher in blacks compared to whites (age-adjusted mean: 13.1 vs 10.2 μg/dL in men [ P &lt;0.001] and 12.7 vs. 8.1 μg/dL in women [ P &lt;0.001]). Serum cortisol was positively related to age and smoking in blacks, DM, menopausal status and use of hormonal therapy (replacement or contraception) in both racial groups (P &lt;0.005). Body mass index and glomerular filtration rate were inversely associated with cortisol in whites and blacks (P &lt;0.01). The age- and sex-adjusted heritability of serum cortisol was 0.20 in whites and 0.11 in blacks ( P ≤0.005). Serum cortisol was not associated with outcomes ( Table ). In blacks, concomitantly high cortisol (&gt;median) and high aldosterone (&gt;median) was associated with incident HTN (odd ratio [OR]: 1.90 [95%CI: 1.14, 3.16]) and DM (1.75 [1.17, 2.62]) compared to normal aldosterone and cortisol; ORs in whites were 1.15 (0.81, 1.63) for HTN and 0.95 (0.52, 1.74) for DM. Conclusions: Serum cortisol is a heritable trait influenced by clinical factors. Conjointly high aldosterone and cortisol levels in blacks is associated with increased risk of HTN and DM in blacks, not in whites.

Factors influencing the age at onset in familial frontotemporal lobar dementia: Important weight of genetics.

Objective:To quantify the effect of genetic factors and generations influencing the age at onset (AAO) in families with frontotemporal lobar dementia (FTD) due to C9ORF72 hexanucleotide repeat expansions and GRN mutations.Methods:We studied 504 affected individuals from 133 families with C9ORF72 repeat expansions and 90 FTD families with mutations in GRN, 2 major genes responsible for FTD and/or amyotrophic lateral sclerosis. Intrafamilial correlations of AAO were analyzed, and variance component methods were used for heritability estimates. Generational effects on hazard rates for AAO were assessed using mixed-effects Cox proportional hazard models.Results:A generational effect influencing AAO was detected in both C9ORF72 and GRN families. Nevertheless, the estimated proportion of AAO variance explained by genetic factors was high in FTD caused by C9ORF72 repeat expansions (44%; p = 1.10e−4), 62% when the AAO of dementia was specifically taken into account (p = 8.10e−5), and to a lesser degree in GRN families (26%; p = 0.17). Intrafamilial correlation analyses revealed a significant level of correlations in C9ORF72 families according to the degree of kinship. A pattern of intrafamilial correlations also suggested potential X-linked modifiers acting on AAO. Nonsignificant correlation values were observed in GRN families.Conclusions:Our results provide original evidence that genetic modifiers strongly influence the AAO in C9ORF72 carriers, while their effects seem to be weaker in GRN families. This constitutes a rational to search for genetic biomarkers, which could help to improve genetic counseling, patient care, and monitoring of therapeutic trials.