Genome wide association and pathway analysis of segment-specific carotid intima-media thickness phenotypes: The San Antonio Family Heart Study

Here is the abstract for the paper I will be presenting at the Human Biology Meetings in Minneapolis.

Intima-media thickness (IMT) of the common and internal carotid arteries is a well known marker of subclinical atherosclerosis and a strong predictor of heart disease and stroke. IMT differs between ethnic populations and higher incidences of stroke have been demonstrated in Hispanics. The objective of this study was to conduct genome-wide association (GWA) and biological pathway analysis of IMT measurements in Mexican American participants from the San Antonio Family Heart study (SAFHS). B-mode carotid ultrasound was performed among 772 SAFHS participants and the near and far wall of the common and internal carotid artery were measured. GWA (based on Illumina’s HumanHap 550K BeadChip) was performed under an additive measured genotype association model, accounting for the non-independence of family members with a random effects kinship model. Models were corrected for age, sex, systolic blood pressure, BMI, diabetes, diabetes medication, and lipids. No significant associations were detected after correcting for multiple-testing (p=5.0x10^-8). The strongest suggestive association was observed on chromosome 15q24 at rs4886741 for carotid artery far wall IMT (P=3.6x10^-7) within an intergenic region. Nominally significant SNPs (p<0.01) were then entered into Ariadne Pathways Studio to identify relevant biological pathways and to investigate how the assignment of intergenic SNPs to genes might impact these results. The WNT-signaling (p=7.8x10^-5) pathway remained significant for both the internal and common carotid arteries under a variety of analysis scenarios. We conclude that through investigation of nominally significant SNPs we are able to detect biological pathways influencing IMT in SAFHS participants.

The Friday Five #3

So now that I'm back at work - Here are Five things I've been checking out this week.

1) Family-Based Bivariate Association Tests for Quantitative Traits: I've actually working on something similar for a paper I'm working on so we will see how different the tests are.

The availability of a large number of dense SNPs, high-throughput genotyping and computation methods promotes the application of family-based association tests. While most of the current family-based analyses focus only on individual traits, joint analyses of correlated traits can extract more information and potentially improve the statistical power. However, current TDT-based methods are low-powered. Here, we develop a method for tests of association for bivariate quantitative traits in families. In particular, we correct for population stratification by the use of an integration of principal component analysis and TDT. A score test statistic in the variance-components model is proposed. Extensive simulation studies indicate that the proposed method not only outperforms approaches limited to individual traits when pleiotropic effect is present, but also surpasses the power of two popular bivariate association tests termed FBAT-GEE and FBAT-PC, respectively, while correcting for population stratification. When applied to the GAW16 datasets, the proposed method successfully identifies at the genome-wide level the two SNPs that present pleiotropic effects to HDL and TG traits.

2) A statistical evaluation of models for the initial settlement of the American continent emphasizes the importance of gene flow with Asia. This one is from a couple of months ago but still is relevant and it came up recently. Overall I agree with the idea that there really hasn't been a true barrier between the Americas and Asia since the Pleistocene as people have crossed over both ways since the Pleistocene.

While there is agreement in that the Bering Strait was the entry point for the initial colonization of the American continent, there is considerable uncertainty regarding the timing and pattern of human migration from Asia to America. In order to perform a statistical assessment of the relative probability of alternative migration scenarios and to estimate key demographic parameters associated with them, we used an Approximate Bayesian Computation (ABC) framework to analyze a dataset of 401 autosomal microsatellite loci typed in 29 Native American populations. A major finding is that a single, discrete, wave of colonization is highly inconsistent with observed levels of genetic diversity. A scenario with two discrete migration waves is also not supported by the data. The current genetic diversity of Amerindian populations is best explained by a third model involving recurrent gene flow between Asia and America, after initial colonization. We estimate that this colonization involved about 100 individuals and occurred some 13,000 years ago; in agreement with well established archeological data.

3) Evaluation of Group Genetic Ancestry of Populations from Philadelphia and Dakar in the Context of Sex-Biased Admixture in the Americas

Background

Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans.

Principal Findings

We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of ~12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9–10% mtDNAs and ~31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas.

Conclusions

We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.

4) The Growing Backlash Against Overparenting: An interesting article from Time on "Overparenting" and parents who now want their kids have a childhood.

5) Chubacabra or Monkey?

PD: Day 73 - GWA and bilirubin

J and I wake up around 6:30. Snarfleblat girl L has kept everybody up. She seems to have some form of allergy going on. Kind of a pain but she is so happy most days it is kind of upsetting to see a little L uncomfortable. That and I'm superparonoid about SIDS since a nephew died from it when I was younger. When S was born I used to wake up every 20 minutes to make sure he was breathing, and with X I used to sleep with my hand on his chest to make sure he was breathing. I chilled a little with C, and now I'm pretty sure it won't happen but it is always in the back of my mind.

J and I decide to start on Memorial Day to July 4th forced exercise regimine. I would like to lose a little weight or at least part of this spare tire I'm carrying around. So we start once again with the Lesley Sanson Walking Away the Pounds. Aargh, I'm so out of shape it is not even funny. Then we have a cup of coffee and I get ready for work. The kids rouse, except for C, who did a Linda Blair the night before and kept us up for a couple of hours, while demanding water. She certainly is bossy for a 2 year old. Although it is supercute when she wrinkles her nose like Samantha from Bewitched and gets angry. I'm a pushover anyway. Then it is off to work.

I spend the day working on the edits to the bilirubin paper. A new week, a new journal, a new format. We are going to avoid the medical journals and head back to a genetic journal. Of course bilirubin has become popular. There are a couple of GWA papers and like I said last week a conditional linkage paper. I won't go into too much detail but there appears to be some key population differences in this particular gene and the fact that elevated bilirubin levels may make you safe from heart disease, they also put you at risk for gall bladder disease and if you have cancer it can negatively react with a host of chemotheuropeutics. So kind of double edged sword - so the idea of personal medicine is fraught with some dangerous outcomes. I also enter all my references into RefWorks, which is an on-line version bibliographic program. I'm getting tired of have to rearrange my references all the time. I'm not used to working with so it is kind of a pain but once I get to work, it is kind of nice. Of course it takes time to enter all these and then put them in the paper. I get most of the way through it and rearrange some things and am almost add some more data. Then I head home.

I get home and we have dinner. The kids are boycotting the evening meal, and have been plotting the overthrow of their parents all day. Apparently, J heads out to pick up a few books from the library. I attempt to put C to sleep and fail miserably put I do get L to sleep. Then X and S take a bath. After that we head downstairs for story time, then bed. I fall asleep on the couch with C, S, and X. I wake up sometime in the middle of the nigh and take C upstairs and lay down on the floor next to her bed until she goes back to sleep. Then off to bed to sleep.

Gene of the Month Club - STK39

Background - Encodes a serine/threonine kinase believed to function in the cellular stress response pathway. Activated in response to hypotonic (movement of water into a cell) stress , leading to phosphorylation of several cation-chloride-coupled co-transporters. The kinase specifically activates the p38 MAP kinase pathway, and its interaction with p38 decreases upon cellular stress. This suggests that this kinase may serve as an intermediate in the response to cellular stress.

In the News: Science Daily had a news article on this gene in relation to hypertension in the Old Order Amish. I like how gene association studies are referred to as a new technique. Not really they have been around for awhile. I however do like that they use a religious isolate for this study as opposed just a phenotype between carriers of the locus versus those who don't. Through the use of families you reduce Type 1 statistical error (for a good review, check out this article).

In the Literature - Here is a link to a recent study in PNAS that is referred to in the news article.