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October 3, 2012

Thinking about heritability

Filed under: Genetics,Genomics,Missing Heritability — Razib Khan @ 12:04 am


The heritability of a trait within a population is the proportion of observable differences in a trait between individuals within a population that is due to genetic differences. Factors including genetics, environment and random chance can all contribute to the variation between individuals in their observable characteristics (in their “phenotypes”)…Heritability thus analyzes the relative contributions of differences in genetic and non-genetic factors to the total phenotypic variance in a population. For instance, some humans in a population are taller than others; heritability attempts to identify how much genetics are playing a role in part of the population being extra tall.

Over at Haldane’s Sieve Dr. Joseph Pickrell has a commentary up on a preprint on explaining the ‘missing heritability’ using yeast genetics. All good reading. I long ago gave up on the idea that the idea of ‘heritability’ would ever be widely internalized among the educated public in any precise sense. But we muddle on. The next decade is going to be big for the genomics of complex traits. Or so people keep telling me!

But this gives me the excuse to point to a commentary which you really should read again and again. It is ...

January 9, 2012

More on the “missing heritability” and epistasis

Filed under: Genetics,Genomics,Missing Heritability — Razib Khan @ 9:35 am

Please see Luke Jostins’ posts at Genetic Inference and Genomes Unzipped.

Update: Steve Hsu weighs in. He read the supplements! Mad props.

January 6, 2012

“Missing heritability” – interaction edition

Filed under: Human Genetics,Human Genomics,Missing Heritability — Razib Khan @ 12:55 pm

The Pith: A great deal of important medical genetic differences between people may be due to the nature of interactions of genetic variants.

If you’ve been reading this blog for a while you know that there is a question in genomics right now as to “missing heritability.” The issue is basically that there are traits where patterns of inheritance within the population strongly imply that most of the variation is due to genes, but attempts to ascertain which specific genetic variants are responsible for this variation have failed to yield much. For example, with height you have a trait which is ~80-90 percent heritable in Western populations, which means that the substantial majority of the population wide variation is attributable to genes. But geneticists feel very lucky if they detect a variant which can account for 1 percent of the variance.

One simple explanation, which gains some genomic support, is that variation on these traits is due to innumerable variants widely distributed across the genome. Therefore, a variant of one percent effect may be a rather large one. There are also those who argue that it may be that there are even more very rare, but somewhat larger effect, alleles at work.

Another model is that the “missing heritability” can be solved by reconceptualizing the “genetic architecture” of the trait. This means that currently a major assumption of many models for putatively polygenic traits is that the variation is due to many genes of small effect which modify the trait value in an additive and independent manner. In other words, the genetic architecture in this sense is a linear system. A clear alternative, or complementary, possibility is that there are genetic interactions which are generating deviations from linearity. This would be epistasis, which has different implications depending on the sort of biology you’re talking about (e.g., molecular vs. evolutionary).

A new paper in PNAS makes the case that a lot of the “missing heritability” has to do with the assumption of additivity in many of the models attempting to smoke out associations. But first, let me point to a press release from from GeneWatch:

The study supports earlier findings by GeneWatch UK that much of the heritability of common diseases, calculated using twin studies, may not exist (2). Scientists have been puzzled by the failure of large genetic studies to find genes which explain the “missing heritability” of common diseases such as heart disease and cancer and traits such as height. Typically, 85 to 95 per cent of the expected heritability has not been found. Today’s new study confirms that one explanation may be that interactions between multiple genes would reduce the predicted heritability. These interactions were not properly accounted for by the eugenicist Ronald Fisher who developed the original twin studies method in 1918, and later analysis has not corrected Fisher’s error.

“Claims of a genetic revolution in healthcare have long been based on false assumptions” said Dr Helen Wallace, Director of GeneWatch UK, “If heritability is much lower than expected this means that genetic differences play only a small role in explaining why some individuals get a disease which others do not. Genetic testing can help people with rare disorders but will never be useful to predict and prevent the common diseases that most people get.”

My attention was brought to this by Hellen Wallace herself, who sent a rather bombastic email stating that Eric Lander has come around to her model, where gene-gene interactions loom large. But from reading the paper I think one of the issue that the authors highlight is that there is often a conflation between heritability in the narrow sense, h2, and heritability in the broad sense, H2. h2 accounts for additive genetic variation. The authors seem to be making the case that you may have to focus on heritability in the broad sense. They state: “Broad-sense heritability H2 measures the full contribution of genes… H2 is the relevant quantity for clinical risk assessment, because it measures our ultimate ability to predict phenotype from genotype.”

I have characterized GeneWatch as “Genetic Creationists” before, and that is because of their misrepresentations and exaggerations. A close reading of this paper does not seem to align at all with their agenda, though it does imply that attempts to map genotype to phenotype are going to be hard. Let me jump to the paper’s conclusion:

Finally, notwithstanding our focus here, we believe that concerns about missing heritability should not distract from the fundamental goals of medical genetics. Human genetic studies to discover variants associated with common traits should primarily be regarded as the analog to mutant hunts in model organisms, with the primary purpose being to identify the underlying pathways and processes. The key focus should be to study the biological role of the variants discovered so far. The proportion of phenotypic variance explained by a variant in the human population is a notoriously poor predictor of the importance of the gene for biology or medicine. [A classic example is the gene encodingHMGCoA reductase, which explains only a tiny fraction of the variance in cholesterol levels but is a powerful target for cholesterol-lowering drugs (1).] Ultimately, the most important goal for biomedical research is not explaining heritability—that is, predicting personalized patient risk—but understanding pathways underlying disease and using that knowledge to develop strategies for therapy and prevention.

You can read the full paper at PNAS, it’s open access. But really you have to go through the supplements, and I’ve only read a few sections of that. Do I believe this? I think the model works out. Frankly, I wanted to check the acknowledgments, and the people listed there give me confidence that the theory here is legitimate, even if you don’t work out the equations yourself. But is this empirically the case? That’s a different issue altogether. The authors note that there will be follow up papers soon. What I will be curious about is the extent of differences in interaction effects by trait. A supplementary table gives us a taste. You see correlations for monozygotic and dizygotic twins. In an additive model the third row should be ~ 0. Look at birth weight and voting behavior, and contrast it with height and IQ.

Citaion: The mystery of missing heritability: Genetic interactions create phantom heritability, doi:10.1073/pnas.1119675109

May 9, 2011

Pygmies are short because nature made them so

Aka Pygmies

The Pith: There has been a long running argument whether Pygmies in Africa are short due to “nurture” or “nature.” It turns out that non-Pygmies with more Pygmy ancestry are shorter and Pygmies with more non-Pygmy ancestry are taller. That points to nature.

In terms of how one conceptualizes the relationship of variation in genes to variation in a trait one can frame it as a spectrum with two extremes. One the one hand you have monogenic traits where the variation is controlled by differences on just one locus. Many recessively expressed diseases fit this patter (e.g., cystic fibrosis). Because you have one gene with only a few variants of note it is easy to capture in one’s mind’s eye the pattern of Mendelian inheritance for these traits in a gestalt fashion. Monogenic traits are highly amenable to a priori logic because their atomic units are so simple and tractable. At the other extreme you have quantitative polygenic traits, where the variation of the trait is controlled by variation on many, many, genes. This may seem a simple ...

December 22, 2010

Heritability and genes as causes

Filed under: Genetics,Genomics,Heritability,Missing Heritability — Razib Khan @ 11:25 am

Since the beginning of this weblog (I’ve been writing for eight years) heritability has been a major confusion. Even long time readers misunderstand what I’m trying to get at when I talk about heritability. That’s why posts such as Mr. Luke Jostins‘ are so helpful. I had seen references to a piece online, The Causes of Common Diseases are Not Genetic Concludes a New Analysis, but I hadn’t given it much thought. Until Ms. Mary Carmichael’s post DNA, Denial, and the Rise of “Environmental Determinism”. She begins:

Michael Pollan, the well-known writer on food and agriculture, is a smart guy. His arguments tend to be nuanced and grounded in common sense. I like his basic maxim on nutrition – “Eat food. Not too much. Mostly plants” – so much that I recently promoted it in a Newsweek cover story. He’s the last person I’d suspect of reactionary thinking, which is why I wish I didn’t have to say this: Michael Pollan has made a deeply unfortunate mistake.

A few days ago, speaking to his 43,000 followers on Twitter, Pollan linked to an essay written by an environmental advocacy group that spends much of its time fighting the depradations of Big Agriculture. Curiously, the essay wasn’t about ecological destruction or even about agriculture. It was about human genetics. It argued that since genetics currently can’t explain everything about inheritance, genes must not influence the development of disease, and thus the causes of illness must be overwhelmingly environmental (meaning “uninherited” as opposed to “caused by pollution,” though the latter category of factors is part of the former one). This was a little like arguing that your engine doesn’t power your car because sometimes it breaks down in a way that confuses your mechanic — and concluding that gasoline alone is sufficient to make a car with no engine run. But Pollan took the argument at face value. He said it showed “how the gene-disease paradigm appears to be collapsing.” He was troubled that its contentions apparently had gone unnoticed: “Why aren’t we hearing about this?!”

Of course I had seen Dr. Daniel MacArthur’s post Bioscience Resource Project critique of modern genomics: a missed opportunity in my RSS, but when I started reading the rebuttal I immediately thought “Dr. Dan’s interlocutors sound kind of dumb,” and I stopped reading. After reading the post I don’t think they’re dumb, I think they’re being lawyerly. Much of the piece is a rhetorical tour de force in leveraging the prejudices and biases of the intended readership. This is the Intelligent Design version of Left-wing “Blank Slate” Creationism.* They smoothly manipulate real findings in a deceptive shell game intended to convince the public, and shape public policy. Their success is evident in Pollan’s response. “X paradigm appears to be collapsing.” “Why aren’t we hearing about this?” Does this sound familiar? Like Dr. MacArthur I think some of the criticisms within the piece are valid. Despite not being hostile to the maxim “better living through chemistry,” I do think that there has been an excessive trend toward pharmaceutical or surgical “cures” in relation to diseases of lifestyle (anti-depressants, gastric bypass, etc.). But we go down a very dangerous path when we make recourse to shoddy means toward ostensibly admirable ends. This sort of discourse is not sustainable! (just used a buzzword intended to appeal right there!)

I honestly can’t be bothered to say much more when so many others already have. This is a boat I missed. But if some of what I say above isn’t clear, I recommend you read the original essay. Then read Dr. MacArthur and Ms. Carmichael. If you’re hungry for more, Ms. Carmichael has a helpful list of links.

* Left Creationism had its most negative manifestation as Lysenkoism, but it suffuses the outlook of many who fear the emergence of a new Nazi abomination. Leon Kamin in the 1970s even claimed that IQ was not heritable at all! Though he backed off such an extreme position, it shows how confident he was that could claim such a thing.

April 1, 2010

Common variants are commonly unpromising

Filed under: Biology,CNV,Common Variant,Genetics,Genomics,Missing Heritability — Razib Khan @ 12:44 am

Excellent post from Dr. Daniel MacArthur, Common copy number variation doesn’t explain much complex disease risk – but why not?:

The Wellcome Trust Case Control Consortium has just published the results of a massive survey of common, large DNA duplications and deletions (collectively termed copy number variation, or CNVs) in 16,000 patients suffering from complex diseases and 3,000 controls. The results come as no surprise, but are nonetheless disappointing: the study identified absolutely no novel CNVs associated with complex disease. Although three such variants were found to alter disease susceptibility, all three had been identified from previous studies.

The study’s findings suggests that – despite their size – common CNVs play very little role in the etiology of common, complex diseases like rheumatoid arthritis and type 2 diabetes, and researchers will have to look elsewhere to uncover the notorious “missing heritability” for these diseases.

Where to next? The field has already moved on with a new focus on rare variants, which (given the selection-based argument above) seem far more likely to yield useful findings. This year will see the launch of several very large studies taking a variety of approaches to dig into the lower end of the frequency spectrum: imputation using existing data-sets; new genome-wide association chips containing larger numbers of rare SNPs; and large-scale sequencing of candidate genes, whole exomes and even entire genomes. Rare variant discovery has already proved successful in the CNV field, and it seems likely that the next round of CNV association studies will prove enormously more fruitful than this study.

Missing heritability is a major issue. Though I guess it does science some good to have white whales to chase….

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