Sunday, July 23, 2017

Pleiotropy, balancing selection, and all that: heart disease

This paper suggests that some genetic variants which increase risk of coronary artery disease (CAD) have been maintained in the population because of their positive effects in other areas of fitness, such as reproduction.
Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy


Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.

Author summary

How genetic variation contributes to disease is complex, especially for those such as coronary artery disease (CAD) that develop over the lifetime of individuals. One of the fundamental questions about CAD––whose progression begins in young adults with arterial plaque accumulation leading to life-threatening outcomes later in life––is why natural selection has not removed or reduced this costly disease. It is the leading cause of death worldwide and has been present in human populations for thousands of years, implying considerable pressures that natural selection should have operated on. Our study provides new evidence that genes underlying CAD have recently been modified by natural selection and that these same genes uniquely and extensively contribute to human reproduction, which suggests that natural selection may have maintained genetic variation contributing to CAD because of its beneficial effects on fitness. This study provides novel evidence that CAD has been maintained in modern humans as a by-product of the fitness advantages those genes provide early in human lifecycles.
From the paper:
... research in quantitative genetics has shown that rapid adaptation can often occur on complex traits that are highly polygenic [29, 30]. Under the ‘infinitesimal (polygenic) model’, such traits are likely to respond quickly to changing selective pressures through smaller allele frequency shifts in many polymorphisms already present in the population [13, 31].

To test for selection signals for variants directly linked with CAD, we utilized SNP summary statistics from 56 genome-wide significant CAD loci in Nikpay et al. [40], the most recent and largest CAD case-control GWAS meta-analysis to date, to identify 76 candidate genes for CAD (see Methods). Nikpay used 60,801 CAD cases and 123,504 controls ...

For a subset of CAD loci, we found significant quantitative associations between disease risk and selection signals and for each of these the direction of this association was often consistent between populations ...

In the comparison across populations, directionality of significant selection-risk associations tended to be most consistent for populations within the same ancestral group (Fig 1B). For example, in PHACTR1, negative associations were present within all European populations (CEU, TSI, FIN), and in NT5C2 strong positive associations were present in all East Asian populations (CHB, CHD, JPT). Other negative associations that were consistent across all populations within an ancestry group included five genes in Europeans (COG5, ABO, ANKS1A, KSR2, FLT1) and four genes (LDLR, PEMT, KIAA1462, PDGFD) in East Asians. ...

... By comparing positive selection variation with genetic risk variation at known loci underlying CAD, we were able to identify and prioritize genes that have been the most likely targets of selection related to this disease across diverse human populations. That selection signals and the direction of selection-risk relationships varied among some populations suggests that CAD-driven selection has operated differently in these populations and thus that these populations might respond differently to similar heart disease prevention strategies. The pleiotropic effects that genes associated with CAD have on traits associated with reproduction that are expressed early in life strongly suggests some of the evolutionary reasons for the existence of human vulnerability to CAD.
Bonus: ~300 variants control about 20% of total variance in genetic CAD risk. This means polygenic risk predictors will eventually have a strong correlation (e.g., at least ~0.4 or 0.5) with actual risk. Good enough for identification of outliers.
Association analyses based on false discovery rate implicate new loci for coronary artery disease
Nature Genetics (2017) doi:10.1038/ng.3913

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10−8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS2, 3. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold2, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.
This is a recent review article (2016):
Genetics of Coronary Artery Disease ...Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome.

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