Friday Five #14: Ancient Eskimos, Complete Africans, and some Cardiovascular Genetics

OK, so I know I missed last week but I haven't spent the last two weeks learning a number of useful new programs such as R and Photoshop. Specifically, how to make really nice figures in photoshop and how to make nice GWAS Manhattan Plots in R as well as survival analysis so I missed out, plus last weekend was overtaken by a mass house cleaning. Here is the top five from the last two weeks.

1) Ancient human genome sequence of an extinct Palaeo-Eskimo: This was all over the news last week and it is very interesting study as it does get to the ability to look at ancient human genomes. However, if I'm being honest I wasn't overly surpised by the conclusions as they are pretty much the same as they had done in a previous paper on mtDNA and the presence of haplogroup D2a, which is found in Eskimos, Na-dene, and Aleuts. Here is the abstract. Also, my grad advisor was a co-author on the paper, which is pretty cool.

We report here the genome sequence of an ancient human. Obtained from ~4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20×, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.

2) Complete Khoisan and Bantu genomes from southern Africa: So once again we have some entire genomes sequenced, which seems to come about everytime someone does that. Perhaps eventually we will get around to doing some actual population genetics of the variation that has been detected, maybe once the 1000 genomes project reaches completion. Anyway, this just demonstrates the direction that human genetics is heading over the next couple of year. Here is the abstract

The genetic structure of the indigenous hunter-gatherer peoples of southern Africa, the oldest known lineage of modern human, is important for understanding human diversity. Studies based on mitochondrial and small sets of nuclear markers have shown that these hunter-gatherers, known as Khoisan, San, or Bushmen, are genetically divergent from other humans. However, until now, fully sequenced human genomes have been limited to recently diverged populations. Here we present the complete genome sequences of an indigenous hunter-gatherer from the Kalahari Desert and a Bantu from southern Africa, as well as protein-coding regions from an additional three hunter-gatherers from disparate regions of the Kalahari. We characterize the extent of whole-genome and exome diversity among the five men, reporting 1.3 million novel DNA differences genome-wide, including 13,146 novel amino acid variants. In terms of nucleotide substitutions, the Bushmen seem to be, on average, more different from each other than, for example, a European and an Asian. Observed genomic differences between the hunter-gatherers and others may help to pinpoint genetic adaptations to an agricultural lifestyle. Adding the described variants to current databases will facilitate inclusion of southern Africans in medical research efforts, particularly when family and medical histories can be correlated with genome-wide data.

3) Association Between a Literature-Based Genetic Risk Score and Cardiovascular Events in Women: This is an article from JAMA, that really is a little bit of a mess if you ask me. So a little background the area on chromosome 9p21 has been implicated in a number of cardiovascular disorders using GWAS but to date no one is really sure, what gene or genes in the region is having this impact. This study looked at a paltry 101 SNPs that had shown association with a litanly of end points or intermediate phenotypes and of course found nothing significant. For a good critical review of the paper see this blog post at Eurogene. Here is the abstract.

Context While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women.

Objective To test the predictive ability of a literature-based genetic risk score for cardiovascular disease.

Design, Setting, and Participants Prospective cohort of 19 313 initially healthy white women in the Women's Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute's catalog of genome-wide association study results published between 2005 and June 2009.

Main Outcome Measure Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death.

Results A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10^–7 were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III–adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models.

Conclusion After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.

4) APOA1 and APOA4 Gene Polymorphisms Influence the Effects of Dietary Fat on LDL Particle Size and Oxidation in Healthy Young Adults: More Cardiovascular Genetics stuff.

We investigated whether APOA1 and APOA4 genotypes interact with diet to determine changes in LDL size and their susceptibility to oxidative modifications. A total of 97 healthy volunteers each consumed 3 diets for 4 wk: a SFA diet (38% fat, 20% SFA) followed by a low-fat and high-carbohydrate (CHO) diet (30% fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA) diet (38% fat, 22% MUFA) following a randomized crossover design. For each diet, we determined susceptibility to oxidative modifications and LDL size. To investigate the combined effects of the APOA1 G-76A and APOA4 Thr347Ser single nucleotide polymorphisms (SNP), we defined 4 combined genotype groups: GG/ThrThr, GG/ThrSer, GA/ThrThr, and GA/ThrSer. After participants consumed the CHO diet, there was a significant decrease in LDL size with respect to high-fat diets in GG homozygotes for the APOA1 G-76A SNP. However, LDL size did not differ in GA carriers among participants consuming the 3 diets. Carriers of the A allele for this polymorphism had smaller LDL size as well as increased susceptibility to oxidation after the SFA diet than the GG homozygous. Moreover, the interaction between the APO A1 and APOA4 genotypes revealed that individuals with the GA/ThrSer genotype had larger LDL particle size during consumption of the MUFA diet than when they consumed the CHO diet. No differences in LDL oxidation were found in this analysis. Our study supports the concept that SNP in APOA1and APOA4 genes influences atherogenic characteristics of LDL particles in response to diet.

5) Genetic Effects on Carotid Intima-Media Thickness: Systematic Assessment and Meta-Analyses of Candidate Gene Polymorphisms Studied in More Than 5000 Subjects: Yet even more CVG stuff

Background— Carotid intima-media thickness (CIMT) is highly heritable and associated with stroke and myocardial infarction, making it a promising quantitative intermediate phenotype for genetic studies of vascular disease. There have been many CIMT candidate gene association studies, but no systematic review to identify consistent, reliable findings.

Methods and Results— We comprehensively sought all published studies of association between CIMT and any genetic polymorphism. We obtained additional unpublished data and performed meta-analyses for the 5 most commonly studied genes (studied in at least 2 studies in a total of >5000 subjects). We used a 3-step meta-analysis method: meta-analysis of variance; genetic model selection; and random effects meta-analysis of the mean CIMT difference between genotypes. We performed subgroup analyses to investigate effects of ethnicity, vascular risk status, and study size. We accounted for potential reporting bias by assessing qualitatively the possible effects of including unavailable data. Polymorphisms in 3 of the 5 genes (apolipoprotein E, angiotensin I converting enzyme, and 5,10-methylenetetrahydrofolate reductase) had an apparent association with CIMT, but for all these, we found evidence of small study bias. Apolipoprotein E 2/3/4 was the only polymorphism with a persistent, statistically significant but modest association when we restricted analysis to larger studies (>1000 subjects).

Conclusions— Of the most extensively studied polymorphisms, apolipoprotein E 2/3/4 is the only one so far with a convincing association with CIMT. Larger studies than have generally been performed so far may be needed to confirm the associations identified in future genome-wide association studies, and to investigate modification of effect according to characteristics such as ethnicity and vascular risk status.

Enjoy :)