Studies examining whether genetic risk information about common, complex diseases can motivate individuals to improve health behaviors and advance planning have shown mixed results. Examining the influence of different study recruitment strategies may help reconcile inconsistencies.
Secondary analyses were conducted on data from the REVEAL study, a series of randomized clinical trials examining the impact of genetic susceptibility testing for Alzheimer’s disease (AD). We tested whether self-referred participants (SRPs) were more likely than actively recruited participants (ARPs) to report health behavior and advance planning changes after AD risk and APOE genotype disclosure.
Of 795 participants with known recruitment status, 546 (69%) were self-referred and 249 (31%) had been actively recruited. SRPs were younger, less likely to identify as African American, had higher household incomes, and were more attentive to AD than ARPs (all P < 0.01). They also dropped out of the study before genetic risk disclosure less frequently (26% versus 41%, P < 0.001). Cohorts did not differ in their likelihood of reporting a change to at least one health behavior 6 weeks and 12 months after genetic risk disclosure, nor in intentions to change at least one behavior in the future. However, interaction effects were observed where ε4-positive SRPs were more likely than ε4-negative SRPs to report changes specifically to mental activities (38% vs 19%, p < 0.001) and diets (21% vs 12%, p = 0.016) six weeks post-disclosure, whereas differences between ε4-positive and ε4-negative ARPs were not evident for mental activities (15% vs 21%, p = 0.413) or diets (8% versus 16%, P = 0.190). Similarly, ε4-positive participants were more likely than ε4-negative participants to report intentions to change long-term care insurance among SRPs (20% vs 5%, p < 0.001), but not ARPs (5% versus 9%, P = 0.365).
Individuals who proactively seek AD genetic risk assessment are more likely to undergo testing and use results to inform behavior changes than those who respond to genetic testing offers. These results demonstrate how the behavioral impact of genetic risk information may vary according to the models by which services are provided, and suggest that how participants are recruited into translational genomics research can influence findings.
ClinicalTrials.gov NCT00089882 and NCT00462917
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0124-0) contains supplementary material, which is available to authorized users.
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
Heterozygosity; Human; Survival; GWAS
While there has been extensive research developing gene-environment interaction (GEI) methods in case-control studies, little attention has been given to sparse and efficient modeling of GEI in longitudinal studies. In a two-way table for GEI with rows and columns as categorical variables, a conventional saturated interaction model involves estimation of a specific parameter for each cell, with constraints ensuring identifiability. The estimates are unbiased but are potentially inefficient because the number of parameters to be estimated can grow quickly with increasing categories of row/column factors. On the other hand, Tukey’s one degree of freedom (df) model for non-additivity treats the interaction term as a scaled product of row and column main effects. Due to the parsimonious form of interaction, the interaction estimate leads to enhanced efficiency and the corresponding test could lead to increased power. Unfortunately, Tukey’s model gives biased estimates and low power if the model is misspecified. When screening multiple GEIs where each genetic and environmental marker may exhibit a distinct interaction pattern, a robust estimator for interaction is important for GEI detection. We propose a shrinkage estimator for interaction effects that combines estimates from both Tukey’s and saturated interaction models and use the corresponding Wald test for testing interaction in a longitudinal setting. The proposed estimator is robust to misspecification of interaction structure. We illustrate the proposed methods using two longitudinal studies — the Normative Aging Study and the Multi-Ethnic Study of Atherosclerosis.
adaptive shrinkage estimation; gene-environment interaction; longitudinal data; Tukey’s one df test for non-additivity
We assessed if hypertension in pregnancy is associated with elevated CRP levels in later life, possibly reflecting an increased risk of CVD.
Elevated C-reactive protein (CRP) levels have been associated with hypertension in pregnancy and with cardiovascular disease (CVD).
We studied 2463 women from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Subjects were categorized as nulliparous women (n=219), women with a history of normotensive pregnancies (n=1839), or women with a history of a hypertensive pregnancy (n=405). Using multiple linear regression models we compared mean CRP levels among the groups after adjusting for age, race, education, smoking, hypertension, personal history of CHD or stroke, diabetes, dyslipidemia, statins, hormone replacement therapy, and family history of CHD or stroke. As CRP levels may be influenced by body mass index (BMI), the model was fit both with and without adjusting for BMI.
There was no significant difference in CRP levels between nulliparous women and those with a history of normotensive pregnancies, either with (p=0.82) or without (p=0.46) adjusting for BMI. In contrast, women with hypertensive pregnancies, compared to those with normotensive pregnancies, had higher CRP levels, both with (p=0.009) and without (p<0.001) adjusting for BMI.
A history of hypertension in pregnancy is associated with elevated CRP levels later in life, independent of traditional CVD risk factors and BMI. An elevated CRP may reflect an inflammatory state in women with a history of hypertensive pregnancy disorders who are at increased risk for CVD.
hypertension; pregnancy; CRP; cardiovascular disease
Hyperhomocysteinemia is associated with an elevated cardiovascular disease risk. We examined whether women with a history of hypertension in pregnancy are more likely to have a high level of serum homocysteine decades after pregnancy.
Serum homocysteine was measured at a mean age of 60 years in nulliparous women (n = 216), and women with a history of normotensive (n = 1825) or hypertensive (n = 401) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Relationships between homocysteine and pregnancy history were examined by linear and logistic regression, controlling for multiple covariates including personal and family history of hypertension, diabetes, obesity, tobacco use, and demographics.
A history of hypertension in pregnancy, when compared with normotensive pregnancy, was associated with a 4.5% higher serum homocysteine level (P = .015) and 1.60-fold increased odds of having an elevated homocysteine (95% confidence interval, 1.15–2.21; P = .005) after adjusting for potentially confounding covariates. In contrast, a history of normotensive pregnancy, as compared with nulliparity, was associated with a 6.1% lower serum homocysteine level (P = .005) and a 0.49-fold reduced odds of elevated homocysteine levels (95% confidence interval, 0.32–0.74; P < .001).
Homocysteine levels decades after pregnancy are higher in women with a history of pregnancy hypertension, even after controlling for potential confounders. Thus, pregnancy history may prompt homocysteine assessment and risk modification in an attempt at primary prevention of cardiovascular disease.
biomarker; cardiovascular disease; homocysteine; hypertension in pregnancy; preeclampsia
Diabetic nephropathy (DN) has become one of the most common causes of end-stage renal disease (ESRD) in many countries, such as 44.5% in Taiwan. Previous studies have shown that there is a genetic component to ESRD. Studies attempting to determine which genetic variants are related to DN in Han Chinese are limited. A case–control study was conducted to identify DN susceptibility variants in Han Chinese patients with type 2 diabetes.
We included 574 unrelated type 2 diabetes patients (217 DN cases and 357 controls), who were genotyped using Illumina HumanHap550-Duo BeadChip. In single-SNP association tests, the SNPs rs11647932, rs11645214, and rs6499323 located at 16q22.1 under the additive-effect disease model were significantly associated with an approximately 2-fold increased risk of DN. In haplotype association tests, identified haplotypes located in the chromosome 16q22.1 region (containing ST3GAL2, COG4, SF3B3, and IL34 genes) raised DN risk. The strongest association was found with haplotype rs2288491-rs4985534-rs11645214 (C-C-G) (adjusted odds ratio [AOR] 1.93, 95% confidence interval [CI] 1.83-2.03, p = 6.25 × 10−7), followed by haplotype rs8052125-rs2288491-rs4985534-rs11645214 (G-C-C-G) (AOR 1.92, 95% CI 1.82-2.02, p = 6.56 × 10−7), and haplotype rs2303792-rs8052125-rs2288491-rs4985534-rs11645214 (A-G-C-C-G) (AOR 1.91, 95% CI 1.81-2.01, p = 1.15 × 10−6).
Our results demonstrate that the novel SNPs and haplotypes located at the 16q22.1 region may involve in the biological pathways of DN in Han Chinese patients with type 2 diabetes. This study can provide new insights into the etiology of DN.
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Diabetic nephropathy; Single-nucleotide polymorphism; Haplotype; Han Chinese
Large population biobanks, important resources for genomic research, also present ethical challenges. The Michigan BioTrust for Health makes dried bloodspots (DBS) leftover from newborn screening, including ~4.5 million collected before 2010 without written consent, available for health research. Absent prospectively gathered consent and/or current engagement with 18- to 29-year olds, little is known about opinions and beliefs from this age group about use of the bloodspots for research. We engaged 2,101 students—BioTrust participants and their peers—at information booths at 20 college campuses across the state to educate youth about the BioTrust and gather information about consent preferences and about hopes and concerns about this public health program. We surveyed student stakeholder DBS research consent preferences and fielded a “postengagement” survey to gauge the attitudes of participants and to evaluate the campus engagement. The most prevalent themes in open-ended comments were support for biobank research and concern that Michiganders are not aware of their participation. While 78 % of students said they would, if asked, opt in to the BioTrust, half of these preferred to be contacted each time a researcher sought to use their DBS. Students reported great interest in the topic and strong likelihood to share what they had learned. BioTrust participants are interested in learning about their role in an initiative whose goals they widely support. Public engagement is particularly important to biobank participants who, absent traditional consent practices, are unaware of their participation. Health-fair style engagements were effective for targeting college-aged stakeholders, communicating complex messages, and likely increasing knowledge. Retrospective biobanks and biobanks that collect proxy consent need policies to respect those who would opt out and will need resources to educate participants and conduct community outreach that is a safeguard to public trust.
Electronic supplementary material
The online version of this article (doi:10.1007/s12687-014-0190-4) contains supplementary material, which is available to authorized users.
Biobank; Public health; Informed consent; Newborn screening; Public attitudes; Community engagement; Public health education
Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity.
As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study’s Offspring Cohort (N = 1,140).
We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455).
Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.
Epidemiology; Genetics of cardiovascular disease; Atherosclerosis risk factors; Other arteriosclerosis
Cigarette smoking is an environmental risk factor for many chronic diseases, and disease risk can often be managed by smoking control. Smoking can induce cellular and molecular changes, including epigenetic modification, but the short-term and long-term epigenetic modifications caused by cigarette smoking at the gene level have not been well understood. Recent studies have identified smoking-related DNA methylation (DNAm) sites in Caucasians. To determine whether the same DNAm sites associate with smoking in African Americans, and to identify novel smoking-related DNAm sites, we conducted a methylome-wide association study of cigarette smoking using a discovery sample of 972 African Americans, and a replication sample of 239 African Americans with two array-based methods. Among fifteen DNAm sites significantly associated with smoking after correction for multiple testing in our discovery sample, five DNAm sites are replicated in an independent cohort, and fourteen sites in the replication sample have effects in the same direction as in the discovery sample. The top two smoking-related DNAm sites in F2RL3 (factor II receptor-like 3) and GPR15 (G-protein-coupled receptor 15) observed in African Americans are consistent with previous findings in Caucasians. The associations between the replicated DNAm sites and smoking remain significant after adjusting for genetic background. Despite the distinct genetic background between African Americans and Caucasians, the DNAm from the two ethnic groups shares common associations with cigarette smoking, which suggests a common molecular mechanism of epigenetic modification influenced by environmental exposure.
Methylome; epigenetic epidemiology; leukocyte; replication; cigarette smoking
We aimed to compare renal function, by estimated GFR, and albuminuria, in three groups of women: nulliparous women, women with a history of normotensive pregnancies, and women with a history of at least one hypertensive pregnancy. Women who participated in the second Family Blood Pressure Program Study visit (2000–2004) and had serum creatinine and urine albumin measurements (n=3015) were categorized as having had no pregnancy lasting greater than 6 months (n=341), having had only normotensive pregnancies (n=2199), or having at least 1 pregnancy with hypertension (n=475) based on a standardized questionnaire. Women who reported having had at least one pregnancy with hypertension were significantly more likely to be hypertensive (75.6% vs. 59.4%, p <0.001), diabetic (34.2% vs. 27.3%, p= < 0.001) and have higher body mass index (32.8 vs. 30.5, p < 0.001) than those who reported normotensive pregnancies. There was a significantly greater risk of microalbuminuria (urine albumin-creatinine ratio greater than 25 mg/g) in those who reported at least one pregnancy with hypertension (OR 1.37, CI 1.02–1.85, p=0.04) than in those with normotensive pregnancies, after adjusting for risk factors for chronic kidney and cardiovascular disease. Hypertension in pregnancy is associated with an increased risk of future microalbuminuria.
Nonalcoholic Fatty Liver Disease (NAFLD) is an obesity-related condition affecting over 50% of individuals in some populations and is expected to become the number one cause of liver disease worldwide by 2020. Common, robustly associated genetic variants in/near five genes were identified for hepatic steatosis, a quantifiable component of NAFLD, in European-ancestry individuals. Here we tested whether these variants were associated with hepatic steatosis in African and/or Hispanic Americans and fine-mapped the observed association signals. We measured hepatic steatosis using computed tomography in five African-American (n=3124) and one Hispanic-American (n=849) cohorts. All analyses controlled for variation in age, age2, gender, alcoholic drinks, and population substructure. Heritability of hepatic steatosis was estimated in three cohorts. Variants in/near PNPLA3, NCAN, LYPLAL1, GCKR, and PPP1R3B were tested for association with hepatic steatosis using a regression framework in each cohort and meta-analyzed. Fine-mapping across African-American cohorts was conducted using meta-analysis. African- and Hispanic-American cohorts were 33.9/37.5% male, with average age of 58.6/42.6 years and body mass index of 31.8/28.9kg/m2, respectively. Hepatic steatosis was 0.20–0.34 heritable in African-and Hispanic-American families (p<0.02 in each cohort). Variants in or near PNPLA3, NCAN, GCKR, PPP1R3B in African Americans and PNPLA3 and PPP1R3B in Hispanic Americans were significantly associated with hepatic steatosis; however, allele frequency and effect size varied across ancestries. Fine-mapping in African Americans highlighted missense variants at PNPLA3 and GCKR and redefined the association region at LYPLAL1.
We show for the first time that multiple genetic variants are associated with hepatic steatosis across ancestries and explain a substantial proportion of the genetic predisposition in African and Hispanic Americans. Missense variants in PNPLA3 and GCKR are likely functional across multiple ancestries.
liver steatosis; single nucleotide polymorphisms; obesity; meta-analysis; genetic variance
An ankle-brachial index (ABI) (the ratio of ankle to brachial artery systolic blood pressure) value ≤0.9 identifies patients with peripheral arterial disease (PAD) and elevated cardiovascular event risk. This study examined whether women with a history of hypertension in pregnancy are more likely to have an ABI ≤0.9 decades after pregnancy.
Methods and Results
ABI was measured in nulliparous women (n=144), and women with a history of normotensive (n=1,272) or hypertensive (n=281) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study [non-Hispanic white (39%) and black (61%) women, 60 (mean) ± 10 (SD) years of age]. Relationships between PAD and pregnancy history were examined by logistic regression. Compared to women with a history of normotensive pregnancy, women with a history of hypertensive pregnancy had greater odds of PAD (1.61 (odds ratio); 1.04–2.49 (95% confidence interval), p=0.03, adjusted for age, race, height and heart rate). Additional adjustment for ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education did not attenuate this relationship (1.63; 1.02–2.62, p=0.04). PAD risk did not differ between women with a history of normotensive pregnancy and nulliparous women (1.06; 0.52–2.14, p=0.87).
Hypertension in pregnancy is an independent risk factor for PAD decades after pregnancy after adjusting for race, age, height, heart rate, ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education.
hypertension in pregnancy; peripheral vascular disease; ankle-brachial index
Some large population biobanks that house biospecimens and health information for research seek broad consent from participants, while others re-consent for specific new studies. Understanding research participants’ attitudes and preferences about broad and narrow consent may improve recruitment, retention, and public support.
An online survey was conducted among a representative sample of 4,659 US adults to examine relationships between consent preferences and demographic factors, beliefs about privacy, the value of research, and the perceived trustworthiness of researchers.
Participants preferred broad consent (52%) over study-by-study consent models (48%). Higher preferences for study-by-study consent observed among Black non-Hispanic respondents, and respondents with lower income and education were explained by differences in the prevalence of one or more beliefs about the study. Respondents with fears about research and those that would feel respected if asked for permission for each research use preferred study-by-study consent. Preference for broad consent was related to the desire not to be bothered with multiple requests and the belief that the study could lead to improved treatments, cures, and lives saved.
These data suggest that support for broad consent is contingent on sufficient information about data use. Work with research participants and community leaders to understand, respond to, and influence opinions about a given, ongoing study may improve uptake of broad consent.
Informed consent; large population studies; biobank; broad consent; public engagement
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
Biobanks raise challenges for developing ethically sound and practicable consent policies. Biobanks comprised of dried bloodspots (DBS) left over from newborn screening, maintained for long-term storage, and potential secondary research applications are no exception. Michigan has been a leader in transforming its DBS collection, marketing its biobank of de-identified samples for health research use. The Michigan BioTrust for Health includes approximately 4 million unconsented retrospective samples collected as early as 1984 and prospective samples added since the fall of 2010 with blanket parental consent. We engaged Michigan citizens to ascertain public attitudes, knowledge, and beliefs about the BioTrust and informed consent. A convenience sampling of 393 participants from communities around the state of Michigan (oversampling for minority populations) participated in meetings addressing newborn screening, the BioTrust and informed consent, yielding quantitative and qualitative survey and discussion data. Participants affirmed the principle of voluntary informed participation in research and advocated for greater public awareness of the existence of the BioTrust. Most expressed support for the use of DBS for research and a desire for greater involvement in granting permission for research use. Opinions varied as to which specific research uses were acceptable. Participants indicated a desire for greater engagement, public awareness, and more active decision making on the part of biobank participants and parents. Diversity of opinion over which research areas were deemed acceptable problematizes the blanket consent model that currently applies to the BioTrust’s prospective DBS collection and that could become the new norm for research using de-identified data under proposed changes to the Common Rule.
Electronic supplementary material
The online version of this article (doi:10.1007/s12687-013-0162-0) contains supplementary material, which is available to authorized users.
Biobank; Public health; Informed consent; Newborn screening; Community engagement
Genome-wide association studies (GWAS) are a popular approach for identifying common genetic variants and epistatic effects associated with a disease phenotype. The traditional statistical analysis of such GWAS attempts to assess the association between each individual Single Nucleotide Polymorphism (SNP) and the observed phenotype. Recently, kernel machine-based tests for association between a SNP set (e.g., SNPs in a gene) and the disease phenotype have been proposed as a useful alternative to the traditional individual SNP approach, and allow for flexible modeling of the potentially complicated joint SNP effects in a SNP set while adjusting for covariates. We extend the kernel machine framework to accommodate related subjects from multiple independent families, and provide a score-based variance component test for assessing the association of a given SNP set with a continuous phenotype, while adjusting for additional covariates and accounting for within-family correlation. We illustrate the proposed method using simulation studies and an application to genetic data from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.
Family association studies; Kernel machine; Linear mixed model; Multi-locus test; Score statistics; Variance component test; Within family correlation
Matrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A Threonine to Alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction (MI) and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a non-invasive measure of subclinical coronary atherosclerosis.
Methods and Results
In 605 Epidemiology of Coronary Artery Calcification Study participants, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relationship between MGP Thr83Ala and CAC progression (P=0.001). In the fully-adjusted model, every one Ala83 allele increase was associated with an estimated 1.9% (95% CI: 0.7%, 3.0%) per one-year since baseline larger increase in CAC quantity. A proxy SNP for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) Study.
Increased risk of MI associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.
Population; Genetics; Atherosclerosis; Calcium; Imaging
Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study.
Methods and Results
Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN.
In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.
echocardiography; ethnic; genome-wide association studies; Left atrium genetics; left ventricular mass genetics
The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
Chronic kidney disease (CKD) is an increasing concern in the United States due to its rapidly rising prevalence, particularly among African Americans. Epigenetic DNA methylation markers are becoming important biomarkers of chronic diseases such as CKD. To better understand how these methylation markers play a role in kidney function, we measured 26,428 DNA methylation sites in 972 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We then evaluated (1) whether epigenetic markers are associated with estimated glomerular filtration rate (eGFR), (2) whether the significantly associated markers are also associated with traditional risk factors and/or novel biomarkers for eGFR, and (3) how much additional variation in eGFR is explained by epigenetic markers beyond established risk factors and biomarkers. The majority of methylation markers most significantly associated with eGFR (24 out of the top 30) appeared to function, at least in part, through pathways related to aging, inflammation, or cholesterol. However, six epigenetic markers were still able to significantly predict eGFR after adjustment for other risk factors. This work shows that epigenetic markers may offer valuable new insight into the complex pathophysiology of CKD in African Americans.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
It is predicted that the rapid acquisition of new genetic knowledge and
related applications during the next decade will have significant implications
for virtually all members of society. Currently, most people get exposed to
information about genes and genetics only through stories publicized in the
media. We sought to understand how individuals in the general population used
and understood the concepts of ‘genetics’ and
‘genes.’ During in-depth one-on-one telephone interviews with
adults in the U.S., we asked questions exploring their basic understanding of
these terms, as well as their belief as to the location of genes in the human
body. A wide-range of responses was received. Despite conversational familiarity
with genetic terminology, many noted frustration or were hesitant when trying to
answer these questions. In addition, some responses reflected a lack of
understanding about basic genetic science that may have significant implications
for broader public education measures in genetic literacy, genetic counseling,
public health practices, and even routine health care.
genetic counseling; genetic education; genetic literacy; public understanding of genetics
Many GWAS have identified novel loci associated with common diseases, but have focused only on main effects of individual genetic variants rather than interactions with environmental factors (GxE). Identification of GxE interactions is particularly important for coronary heart disease (CHD), a major preventable source of morbidity and mortality with strong non-genetic risk factors. Atherosclerosis is the major cause of CHD, and coronary artery calcification (CAC) is directly correlated with quantity of coronary atherosclerotic plaque. In the current study, we tested for genetic variants influencing extent of CAC via interaction with smoking (GxS), by conducting a GxS discovery GWAS in Genetic Epidemiology Network of Arteriopathy (GENOA) sibships (N = 915 European Americans) followed by replication in Framingham Heart Study (FHS) sibships (N = 1025 European Americans). Generalized estimating equations accounted for the correlation within sibships in strata-specific groups of smokers and nonsmokers, as well as GxS interaction. Primary analysis found SNPs that showed suggestive associations (p≤10−5) in GENOA GWAS, but these index SNPs did not replicate in FHS. However, secondary analysis was able to replicate candidate gene regions in FHS using other SNPs (+/−250 kb of GENOA index SNP). In smoker and nonsmoker groups, replicated genes included TCF7L2 (p = 6.0×10−5) and WWOX (p = 4.5×10−6); and TNFRSF8 (p = 7.8×10−5), respectively. For GxS interactions, replicated genes included TBC1D4 (p = 6.9×10−5) and ADAMTS9 (P = 7.1×10−5). Interestingly, these genes are involved in inflammatory pathways mediated by the NF-κB axis. Since smoking is known to induce chronic and systemic inflammation, association of these genes likely reflects roles in CAC development via inflammatory pathways. Furthermore, the NF-κB axis regulates bone remodeling, a key physiological process in CAC development. In conclusion, GxS GWAS has yielded evidence for novel loci that are associated with CAC via interaction with smoking, providing promising new targets for future population-based and functional studies of CAC development.
A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.