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
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
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.
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
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
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.
A more thorough understanding of the differences in DNA methylation (DNAm) profiles in populations may hold promise for identifying molecular mechanisms through which genetic and environmental factors jointly contribute to human diseases. Inflammation is a key molecular mechanism underlying several chronic diseases including cardiovascular disease, and it affects DNAm profile on both global and locus-specific levels. To understand the impact of inflammation on the DNAm of the human genome, we investigated DNAm profiles of peripheral blood leukocytes from 966 African American participants in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. By testing the association of DNAm sites on CpG islands of over 14,000 genes with C-reactive protein (CRP), an inflammatory biomarker of cardiovascular disease, we identified 257 DNAm sites in 240 genes significantly associated with serum levels of CRP adjusted for age, sex, body mass index and smoking status, and corrected for multiple testing. Of the significantly associated DNAm sites, 80.5% were hypomethylated with higher CRP levels. The most significant Gene Ontology terms enriched in the genes associated with the CRP levels were immune system process, immune response, defense response, response to stimulus, and response to stress, which are all linked to the functions of leukocytes. While the CRP-associated DNAm may be cell-type specific, understanding the DNAm association with CRP in peripheral blood leukocytes of multi-ethnic populations can assist in unveiling the molecular mechanism of how the process of inflammation affects the risks of developing common disease through epigenetic modifications.
Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.
Central obesity is a marker of body fat distribution and is known to have a genetic underpinning. Few studies have reported genome-wide association study (GWAS) results among individuals of predominantly African ancestry (AA). We performed a collaborative meta-analysis in order to identify genetic loci associated with body fat distribution in AA individuals using waist circumference (WC) and waist to hip ratio (WHR) as measures of fat distribution, with and without adjustment for body mass index (BMI). We uncovered 2 genetic loci potentially associated with fat distribution: LHX2 in association with WC-adjusted-for-BMI and at RREB1 for WHR-adjusted-for-BMI. Six of fourteen previously reported loci for waist in EA populations were significant in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). These findings reinforce the concept that there are loci for body fat distribution that are independent of generalized adiposity.
Obesity is a highly heritable trait and a growing public health problem. African Americans are a genetically diverse, yet understudied population with a high prevalence of obesity (body mass index (BMI) greater than 30 kg/m2). Recent studies based upon single nucleotide polymorphisms (SNPs) have identified genetic markers associated with obesity. However, a large proportion of the heritability of obesity remains unexplained. Copy number variation (CNV) has been cited as a possible source of missing heritability in common diseases such as obesity. We conducted a CNV genome-wide association study of BMI in two African American cohorts from GENOA and HyperGEN. We performed independent and identical association analyses in each study, then combined the results in a meta-analysis. We identified three CNVs associated with BMI, obesity, and other obesity-related traits after adjusting for multiple testing. These CNVs overlap the PARK2, GYPA and SGCZ genes. Our results suggest that CNV may play a role in the etiology of obesity in African Americans.
Obesity; CNVs; Meta-analysis; BMI; African Americans
Background and method
We investigated whether chronic kidney disease detected by increased serum creatinine (SCr) or urine albumin-to-creatinine ratio (UACR) may reflect arteriosclerosis involving the kidneys. The sample consisted of 1585 members of sibships (804 non-Hispanic whites and 781 non-Hispanic blacks) in which at least two siblings had primary hypertension. We first evaluated the correlations of increased SCr and UACR with the presence of cerebral small vessel arteriosclerosis, which was determined by increased subcortical white matter hyperintensity (WMH) volume on brain magnetic resonance imaging; and with peripheral large vessel arteriosclerosis, which was determined by decreased ankle-brachial index (ABI). After age adjustment, increased SCr and UACR correlated with increased WMH volume (0.54 and 0.52, respectively) and with decreased ABI (0.50 and 0.54, respectively; all P < 0.001). We then used logistic regression to evaluate the dependency of each measure of disease on conventional risk factors for arteriosclerosis to assess whether the risk factors’ effects were proportional across different measures of disease.
Age, race, sex, hypertension, diabetes, total cholesterol, and smoking made similar overall contributions to the prediction of each measure of disease, as judged by the model C-statistics, which varied in a narrow range from 0.84 to 0.85 (all P < 0.001). However, the relative contributions that the modifiable risk factors, including hypertension, diabetes, total cholesterol, and smoking made to prediction of increased SCr and UACR were disproportionate to their relative contributions to prediction of decreased ABI (P < 0.0001).
The findings support the view that chronic kidney disease detected by increased SCr or UACR primarily reflects small vessel arteriosclerosis involving the kidneys.
albuminuria; ankle-brachial blood pressure index; arteriosclerosis; blood pressure; glomerular filtration rate; hypertension; subcortical white matter hyperintensity
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction, but contributed little to our understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways may be uncovered by accounting for differences in body mass index (BMI) and potential interaction between BMI and genetic variants. We applied a novel joint meta-analytical approach to test associations with fasting insulin (FI) and glucose (FG) on a genome-wide scale. We present six previously unknown FI loci at P<5×10−8 in combined discovery and follow-up analyses of 52 studies comprising up to 96,496non-diabetic individuals. Risk variants were associated with higher triglyceride and lower HDL cholesterol levels, suggestive of a role for these FI loci in insulin resistance pathways. The localization of these additional loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.
Methods and Results
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction
Our goal was to evaluate the influence of quality control (QC) decisions using two genotype calling algorithms, CRLMM and Birdseed, designed for the Affymetrix SNP Array 6.0.
Various QC options were tried using the two algorithms and comparisons were made on subject and call rate and on association results using two data sets.
For Birdseed, we recommend using the contrast QC instead of QC call rate for sample QC. For CRLMM, we recommend using the signal-to-noise rate ≥4 for sample QC and a posterior probability of 90% for genotype accuracy. For both algorithms, we recommend calling the genotype separately for each plate, and dropping SNPs with a lower call rate (<95%) before evaluating samples with lower call rates. To investigate whether the genotype calls from the two algorithms impacted the genome-wide association results, we performed association analysis using data from the GENOA cohort; we observed that the number of significant SNPs were similar using either CRLMM or Birdseed.
Using our suggested workflow both algorithms performed similarly; however, fewer samples were removed and CRLMM took half the time to run our 854 study samples (4.2 h) compared to Birdseed (8.4 h).
Genotype call; Birdseed; CRLMM; Quality control decisions; Association
To determine the relationship between genetic polymorphisms and environmental factors (skin color) on blood pressure among African American women.
A descriptive study, consisting of 137 African American women from a Midwestern, metropolitan area was conducted. Blood pressure was measured using a digital blood pressure monitor. Self-reporting methods were utilized to obtain information on skin color. Buccal swab saliva samples were obtained for genotyping.
Of the four single nucleotide polymorphisms (SNPs) on the sodium bicarbonate co-transporter gene (SLC4A5) examined in this study, only one SNP (rs10177833) and skin color interaction was found to be associated with systolic blood pressure. The additive effect of rs10177833 on systolic blood pressure is statistically different between women with dark skin color and women with medium skin color (P=.0153). No SNP and skin color interaction was found to be associated with blood pressure readings in other SNPs tested (rs8179526, rs6726450 and rs6731545).
These findings of genetic and skin color relatedness to blood pressure is important when considering appropriate diagnostic and treatment plans for African American women with hypertension. African American women with darker skin color may require further assessment for risk factors such as discrimination related stress when being seen by health professionals for hypertension. (Ethn Dis. 2012;22(2):155-161)
Blood Pressure; Genetic; African American; Skin Color