Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 Pjoint < 5 × 10-8), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (Pint < 5 × 10-8). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (Pint = 2 × 10-6). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (Pint < 10-3). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Identifying blood pressure loci whose effects are modulated by multiple lifestyle exposures.

Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene-multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome-wide gene-environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome-wide significant (p < 5 × 10-8 ) and 11 suggestive (p < 1 × 10-6 ) loci. Gene-environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1, and DAPK2. Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene-environment interaction analysis can identify additional loci missed by single lifestyle approaches.

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Correction: Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

[This corrects the article DOI: 10.1371/journal.pgen.1006728.].

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.

The Promise of Selecting Individuals from the Extremes of Exposure in the Analysis of Gene-Physical Activity Interactions.

BACKGROUND: Dichotomization using the lower quartile as cutoff is commonly used for harmonizing heterogeneous physical activity (PA) measures across studies. However, this may create misclassification and hinder discovery of new loci. OBJECTIVES: This study aimed to evaluate the performance of selecting individuals from the extremes of the exposure (SIEE) as an alternative approach to reduce such misclassification. METHOD: For systolic and diastolic blood pressure in the Framingham Heart Study, we performed a genome-wide association study with gene-PA interaction analysis using three PA variables derived by SIEE and two other dichotomization approaches. We compared number of loci detected and overlap with loci found using a quantitative PA variable. In addition, we performed simulation studies to assess bias, false discovery rates (FDR), and power under synergistic/antagonistic genetic effects in exposure groups and in the presence/absence of measurement error. RESULTS: In the empirical analysis, SIEE's performance was neither the best nor the worst. In most simulation scenarios, SIEE was consistently outperformed in terms of FDR and power. Particularly, in a scenario characterized by antagonistic effects and measurement error, SIEE had the least bias and highest power. CONCLUSION: SIEE's promise appears limited to detecting loci with antagonistic effects. Further studies are needed to evaluate SIEE's full advantage.

Three Approaches to Modeling Gene-Environment Interactions in Longitudinal Family Data: Gene-Smoking Interactions in Blood Pressure.

Blood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene-smoking interactions have detected novel BP loci in cross-sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied. Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene-smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations (GEE), hierarchical linear modeling, and pedigree-based mixed modeling. The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single-visit analyses. The pedigree-based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene-smoking interactions. The GEE, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency <1% were included in the analysis. The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data.

An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.

Studying gene-environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

Influence of Smoking Status and Intensity on Discovery of Blood Pressure Loci Through Gene-Smoking Interactions.

BACKGROUND: Genetic variation accounts for approximately 30% of blood pressure (BP) variability but most of that variability has not been attributed to specific variants. Interactions between genes and BP-associated factors may explain some "missing heritability." Cigarette smoking increases BP after short-term exposure and decreases BP with longer exposure. Gene-smoking interactions have discovered novel BP loci, but the contribution of smoking status and intensity to gene discovery is unknown. METHODS: We analyzed gene-smoking intensity interactions for association with systolic BP (SBP) in three subgroups from the Framingham Heart Study: current smokers only (N = 1,057), current and former smokers ("ever smokers," N = 3,374), and all subjects (N = 6,710). We used three smoking intensity variables defined at cutoffs of 10, 15, and 20 cigarettes per day (CPD). We evaluated the 1 degree-of-freedom (df) interaction and 2df joint test using generalized estimating equations. RESULTS: Analysis of current smokers using a CPD cutoff of 10 produced two loci associated with SBP. The rs9399633 minor allele was associated with increased SBP (5 mmHg) in heavy smokers (CPD > 10) but decreased SBP (7 mmHg) in light smokers (CPD ≤ 10). The rs11717948 minor allele was associated with decreased SBP (8 mmHg) in light smokers but decreased SBP (2 mmHg) in heavy smokers. Across all nine analyses, 19 additional loci reached P < 1 × 10(-6). DISCUSSION: Analysis of current smokers may have the highest power to detect gene-smoking interactions, despite the reduced sample size. Associations of loci near SASH1 and KLHL6/KLHL24 with SBP may be modulated by tobacco smoking.

An empirical comparison of meta-analysis and mega-analysis of individual participant data for identifying gene-environment interactions.

For analysis of the main effects of SNPs, meta-analysis of summary results from individual studies has been shown to provide comparable results as "mega-analysis" that jointly analyzes the pooled participant data from the available studies. This fact revolutionized the genetic analysis of complex traits through large GWAS consortia. Investigations of gene-environment (G×E) interactions are on the rise since they can potentially explain a part of the missing heritability and identify individuals at high risk for disease. However, for analysis of gene-environment interactions, it is not known whether these methods yield comparable results. In this empirical study, we report that the results from both methods were largely consistent for all four tests; the standard 1 degree of freedom (df) test of main effect only, the 1 df test of the main effect (in the presence of interaction effect), the 1 df test of the interaction effect, and the joint 2 df test of main and interaction effects. They provided similar effect size and standard error estimates, leading to comparable P-values. The genomic inflation factors and the number of SNPs with various thresholds were also comparable between the two approaches. Mega-analysis is not always feasible especially in very large and diverse consortia since pooling of raw data may be limited by the terms of the informed consent. Our study illustrates that meta-analysis can be an effective approach also for identifying interactions. To our knowledge, this is the first report investigating meta-versus mega-analyses for interactions.

A Paradigm For Calling Sequence In Families: The Long Life Family Study.

Over Several years, we have developed a system for assuring the quality of whole genome sequence (WGS) data in the LLFS families. We have focused on providing data to identify germline genetic variants with the aim of releasing as many variants on as many individuals as possible. We aim to assure the quality of the individual calls. The availability of family data has enabled us to use and validate some filters not commonly used in population-based studies. We developed slightly different procedures for the autosomal, X, Y, and Mitochondrial (MT) chromosomes. Some of these filters are specific to family data, but some can be used with any WGS data set. We also describe the procedure we use to construct linkage markers from the SNP sequence data and how we compute IBD values for use in linkage analysis.

Multi-omics Integration Identifies Genes Influencing Traits Associated with Cardiovascular Risks: The Long Life Family Study.

The Long Life Family Study (LLFS) enrolled 4,953 participants in 539 pedigrees displaying exceptional longevity. To identify genetic mechanisms that affect cardiovascular risks in the LLFS population, we developed a multi-omics integration pipeline and applied it to 11 traits associated with cardiovascular risks. Using our pipeline, we aggregated gene-level statistics from rare-variant analysis, GWAS, and gene expression-trait association by Correlated Meta-Analysis (CMA). Across all traits, CMA identified 64 significant genes after Bonferroni correction (p ≤ 2.8×10-7), 29 of which replicated in the Framingham Heart Study (FHS) cohort. Notably, 20 of the 29 replicated genes do not have a previously known trait-associated variant in the GWAS Catalog within 50 kb. Thirteen modules in Protein-Protein Interaction (PPI) networks are significantly enriched in genes with low meta-analysis p-values for at least one trait, three of which are replicated in the FHS cohort. The functional annotation of genes in these modules showed a significant over-representation of trait-related biological processes including sterol transport, protein-lipid complex remodeling, and immune response regulation. Among major findings, our results suggest a role of triglyceride-associated and mast-cell functional genes FCER1A, MS4A2, GATA2, HDC, and HRH4 in atherosclerosis risks. Our findings also suggest that lower expression of ATG2A, a gene we found to be associated with BMI, may be both a cause and consequence of obesity. Finally, our results suggest that ENPP3 may play an intermediary role in triglyceride-induced inflammation. Our pipeline is freely available and implemented in the Nextflow workflow language, making it easily runnable on any compute platform (https://nf-co.re/omicsgenetraitassociation).

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Mosaic Chromosomal Alterations and Human Longevity.

Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3 642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100 KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared with controls (relative risk 0.637, p = .0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p = .002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p = 5.15e-05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p = .0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages >102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Genome-wide linkage and positional association study of blood pressure response to dietary sodium intervention: the GenSalt Study.

The authors conducted a genome-wide linkage scan and positional association analysis to identify the genetic determinants of salt sensitivity of blood pressure (BP) in a large family-based, dietary-feeding study. The dietary intervention was conducted among 1,906 participants in rural China (2003-2005). A 7-day low-sodium intervention was followed by a 7-day high-sodium intervention. Salt sensitivity was defined as BP responses to low- and high-sodium interventions. Signals of the logarithm of the odds to the base 10 (LOD ≥ 3) were detected at 33-42 centimorgans of chromosome 2 (2p24.3-2p24.1), with a maximum LOD score of 3.33 for diastolic blood pressure responses to high-sodium intervention. LOD scores were 2.35-2.91 for mean arterial pressure (MAP) and 0.80-1.49 for systolic blood pressure responses in this region, respectively. Correcting for multiple tests, single nucleotide polymorphism (SNP) rs11674786 (2.7 kilobases upstream of the family with sequence similarity 84, member A, gene (FAM84A)) in the linkage region was significantly associated with diastolic blood pressure (P = 0.0007) and MAP responses (P = 0.0007), and SNP rs16983422 (2.8 kilobases upstream of the visinin-like 1 gene (VSNL1)) was marginally associated with diastolic blood pressure (P = 0.005) and MAP responses (P = 0.005). An additive interaction between SNPs rs11674786 and rs16983422 was observed, with P = 7.00 × 10(-5) and P = 7.23 × 10(-5) for diastolic blood pressure and MAP responses, respectively. The authors concluded that genetic region 2p24.3-2p24.1 might harbor functional variants for the salt sensitivity of BP.

Gene-lifestyle interactions in the genomics of human complex traits.

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted modest correlation between marginal and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell types. In these analyses, we found multiple instances of potential heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work, we identified potential biases in methods used to jointly meta-analyze genetic and interaction effects. We performed simulations to characterize these limitations and to provide the community with guidelines for future G×E studies.