Associations between self-referral and health behavior responses to genetic risk information

Background: 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. Methods: 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. Results: 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). Conclusions: 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. Trial registration 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

Identification of genes associated with complex traits by testing the genetic dissimilarity between individuals

Using the exome sequencing data from 697 unrelated individuals and their simulated disease phenotypes from Genetic Analysis Workshop 17, we develop and apply a gene-based method to identify the relationship between a gene with multiple rare genetic variants and a phenotype. The method is based on the Mantel test, which assesses the correlation between two distance matrices using a permutation procedure. Using up to 100,000 permutations to estimate the statistical significance in 200 replicate data sets, we found that the method had 5.1% type I error at an α level of 0.05 and had various power to detect genes with simulated genetic associations. FLT1 and KDR had the most significant correlations with Q1 and were replicated 170 and 24 times, respectively, in 200 simulated data sets using a Bonferroni corrected p-value of 0.05 as a threshold. These results suggest that the distance correlation method can be used to identify genotype-phenotype association when multiple rare genetic variants in a gene are involved

Software comparison for evaluating genomic copy number variation for Affymetrix 6.0 SNP array platform

<p>Abstract</p> <p>Background</p> <p>Copy number data are routinely being extracted from genome-wide association study chips using a variety of software. We empirically evaluated and compared four freely-available software packages designed for Affymetrix SNP chips to estimate copy number: Affymetrix Power Tools (APT), Aroma.Affymetrix, PennCNV and CRLMM. Our evaluation used 1,418 GENOA samples that were genotyped on the Affymetrix Genome-Wide Human SNP Array 6.0. We compared bias and variance in the locus-level copy number data, the concordance amongst regions of copy number gains/deletions and the false-positive rate amongst deleted segments.</p> <p>Results</p> <p>APT had median locus-level copy numbers closest to a value of two, whereas PennCNV and Aroma.Affymetrix had the smallest variability associated with the median copy number. Of those evaluated, only PennCNV provides copy number specific quality-control metrics and identified 136 poor CNV samples. Regions of copy number variation (CNV) were detected using the hidden Markov models provided within PennCNV and CRLMM/VanillaIce. PennCNV detected more CNVs than CRLMM/VanillaIce; the median number of CNVs detected per sample was 39 and 30, respectively. PennCNV detected most of the regions that CRLMM/VanillaIce did as well as additional CNV regions. The median concordance between PennCNV and CRLMM/VanillaIce was 47.9% for duplications and 51.5% for deletions. The estimated false-positive rate associated with deletions was similar for PennCNV and CRLMM/VanillaIce.</p> <p>Conclusions</p> <p>If the objective is to perform statistical tests on the locus-level copy number data, our empirical results suggest that PennCNV or Aroma.Affymetrix is optimal. If the objective is to perform statistical tests on the summarized segmented data then PennCNV would be preferred over CRLMM/VanillaIce. Specifically, PennCNV allows the analyst to estimate locus-level copy number, perform segmentation and evaluate CNV-specific quality-control metrics within a single software package. PennCNV has relatively small bias, small variability and detects more regions while maintaining a similar estimated false-positive rate as CRLMM/VanillaIce. More generally, we advocate that software developers need to provide guidance with respect to evaluating and choosing optimal settings in order to obtain optimal results for an individual dataset. Until such guidance exists, we recommend trying multiple algorithms, evaluating concordance/discordance and subsequently consider the union of regions for downstream association tests.</p

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Interactions between the adducin 2 gene and antihypertensive drug therapies in determining blood pressure in people with hypertension

<p>Abstract</p> <p>Background</p> <p>As part of the NHLBI Family Blood Pressure Program, the Genetic Epidemiology Network of Arteriopathy (GENOA) recruited 575 sibships (n = 1583 individuals) from Rochester, MN who had at least two hypertensive siblings diagnosed before age 60. Linkage analysis identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in 7 positional candidate genes, including adducin 2 (<it>ADD2</it>).</p> <p>Method</p> <p>To investigate whether blood pressure (BP) levels in these hypertensives (n = 1133) were influenced by gene-by-drug interactions, we used cross-validation statistical methods (i.e., estimating a model for predicting BP levels in one subgroup and testing it in a different subgroup). These methods greatly reduced the chance of false positive findings.</p> <p>Results</p> <p>Eight SNPs in <it>ADD2 </it>were significantly associated with systolic BP in untreated hypertensives (p-value < 0.05). Moreover, we also identified SNPs associated with gene-by-drug interactions on systolic BP in drug-treated hypertensives. The TT genotype at SNP rs1541582 was associated with an average systolic BP of 133 mmHg in the beta-blocker subgroup and 148 mmHg in the diuretic subgroup after adjusting for overall mean differences among drug classes.</p> <p>Conclusion</p> <p>Our findings suggest that hypertension candidate gene variation may influence BP responses to specific antihypertensive drug therapies and measurement of genetic variation may assist in identifying subgroups of hypertensive patients who will benefit most from particular antihypertensive drug therapies.</p

Metabolic syndrome is associated with change in subclinical arterial stiffness - A community-based Taichung Community Health Study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate the effect of MetS on arterial stiffness in a longitudinal study.</p> <p>Methods</p> <p>Brachial-ankle pulse wave velocity (baPWV), a measurement interpreted as arterial stiffness, was measured in 1518 community-dwelling persons at baseline and re-examined within a mean follow-up period of 3 years. Multivariate linear regression with generalized estimating equations (GEE) were used to examine the longitudinal relationship between MetS and its individual components and baPWV, while multivariate logistic regression with GEE was used to examine the longitudinal relationship between MetS and its individual components and the high risk group with arterial stiffness.</p> <p>Results</p> <p>Subjects with MetS showed significantly greater baPWV at the end point than those without MetS, after adjusting for age, gender, education, hypertension medication and mean arterial pressure (MAP). MetS was associated with the top quartile of baPWV (the high-risk group of arterial stiffness, adjusted odds ratio [95% confidence interval] 1.52 [1.21-1.90]), and a significant linear trend of risk for the number of components of MetS was found (p for trend < 0.05). In further considering the individual MetS component, elevated blood pressure and fasting glucose significantly predicted a high risk of arterial stiffness (adjusted OR [95% CI] 3.72 [2.81-4.93] and 1.35 [1.08-1.68], respectively).</p> <p>Conclusions</p> <p>MetS affects the subject's progression to arterial stiffness. Arterial stiffness increased as the number of MetS components increased. Management of MetS is important for preventing the progression to advanced arterial stiffness.</p