Not so long ago, there was a hope in the research community that common genetic variation, i.e. variants present at minor allele frequencies >5% in human populations, might explain most or all of the heritability of common complex disease. That would have been convenient, because such variants can be genotyped with precise, inexpensive, high-density SNP arrays in tens of thousands of samples.
Sadly, the human genome doesn’t play that way.
Genome-wide association studies have implicated hundreds (if not thousands) of new loci in common complex disease. Yet most of the identified variants had a very small effect on risk, and they collectively explained only a fraction of disease heritability. One possible explanation was that rare variants, which are largely untested by high-density SNP arrays, might account for some of that missing heritability. Yet large-scale sequencing studies of common complex disease have not been financially viable until very recently.
As we forge ahead with the Alzheimer’s Disease Sequencing Project, TopMed, CCDG, and other projects, it’s promising to see results like those in the common/rare variant association study recently published by the International AMD Genomics Consortium.
Age-related Macular Degeneration: A Common Disease
Age-related macular degeneration (AMD) is the leading cause of blindness, affecting about 10 million patients worldwide. It’s a progressive disease whose biological underpinnings are still not well understood, and therapeutic options are limited. Like most age-related diseases, this is a complex phenotype with numerous risk factors, but there’s clearly a substantial inherited component at play.
As of last year, GWAS efforts had uncovered 21 loci in which genetic variation affects disease risk. Translating these into biological insights (or better yet, therapeutic targets) has been challenging.
Massive GWAS: Common and Rare Variants
The International AMD Genomics Consortium (IAMDGC) brought together 16,000 AMD cases and 17,000 controls from 26 different studies, and genotyped them using a customized set of variants:
- Common variants used for classic genome-wide association studies
- Low-frequency coding variants, i.e. “exome chip”
- Protein-altering variants detected by previous AMD gene sequencing studies
Altogether, the authors directly genotyped about 450,000 variants (160,000 of which were protein-altering). After imputation, they were able to analyze 12 million variants overall. Single-variant association testing revealed 34 susceptibility loci for AMD:
The 52 associated variants roughly double the number of genetic loci for AMD. The vast majority of them (42/52) are common, with MAF >1% and relatively small effects on risk. The odds ratio (OR) which measures the relative increase/decrease of risk conferred by such variants, ranges from 1.1-2.9.
The Role of Rare Variants
Yet the authors also observed 7 significantly associated rare variants (MAF<1%) with odds ratios of 1.1-47.6. All seven were located in or near complement genes (that’s “complement” as in the innate immune system complex), which had been implicated in AMD by sequencing studies over the past couple of years. Four genes also exhibited a significant burden of rare damaging variants, suggesting a functional link to disease risk.
Notably, three of those four burden signals were due to variants with frequency <0.1%, suggesting that trait-associated variants with clear functional consequences might be even rarer than we’d guessed. The corollary, of course, is that sample sizes will need to be much larger to detect them with any kind of power.
Shared Genetics for Mendelian and Complex Disease
One of the rare variant burden genes, TIMP3, was previously associated with Sorsby’s fundus dystrophy, a rare disease similar to AMD but with earlier on set and Mendelian inheritance. The Mendelian disease variants occur largely in exon 5, but the IAMDGC’s study uncovered a number of rare variants of the same class (nonsynonymous changes disrupting cysteine residues) in other exons in AMD cases.
Carriers of such alleles also had a burden of other AMD-associated variants, suggesting that TIMP3 variation contributes to disease risk in conjunction with other variants. It’s a cool example of variation in the same gene giving rise to monogenic and complex disorders with similar clinical presentations.
Outlook for Common Disease Genomics
I like this study because it demonstrates the importance of looking at both common and rare variants, in a large number of samples, to more comprehensively interrogate the genome for complex disease loci. It sets the stage for large-scale sequencing of complex disease. We have the tools and we have the sample collections. Now, we just need the funding.
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