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Uncovering the roles of rare variants in common disease through whole-genome sequencing

Key Points

  • Genome-wide association studies of very common variants have neither identified associations that explain a large portion of the heritability for most traits studied nor identified the causal variants behind the associations seen.

  • Although few common variants that cause a disease have been securely identified, rare variants have been found that have strong influences on common diseases: for example, a SNP in type 1 diabetes and copy-number variants in schizophrenia.

  • It seems likely that rare variants, similar in some ways to those identified in Mendelian diseases, will be found that influence common diseases. It is also likely that these rare variants will often influence the coding regions of genes in a manner that is readily recognizable, and will be of large enough effect size to be identified despite their low frequencies.

  • Whole-genome sequencing will provide the best means of identifying rare causal variants. We propose two strategies for studies: resequencing the genomes of individuals with extreme phenotypes and resequencing the genomes of individuals with a familial disease.

  • We predict that whole-genome sequencing will identify rare variants with large effects on many diseases and traits in the coming years. The knowledge that could potentially be gained about these traits, such as the type of mutation and the gene that influences each trait, could provide information for new drug targets.

Abstract

Although genome-wide association (GWA) studies for common variants have thus far succeeded in explaining only a modest fraction of the genetic components of human common diseases, recent advances in next-generation sequencing technologies could rapidly facilitate substantial progress. This outcome is expected if much of the missing genetic control is due to gene variants that are too rare to be picked up by GWA studies and have relatively large effects on risk. Here, we evaluate the evidence for an important role of rare gene variants of major effect in common diseases and outline discovery strategies for their identification.

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Figure 1: Role of deletions in disease predisposition.
Figure 2: Synthetic associations.
Figure 3: Strategies for identifying disease-causing variants.

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Acknowledgements

We thank D. Ge, E. L. Heinzen, A. C. Need, J. C. Fellay, J. M. Maia, E. K. Ruzzo and H. F. Willard for helpful comments on the manuscript.

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Correspondence to David B. Goldstein.

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Glossary

Minor allele frequency

Ranging from 0 to 50%, this is the proportion of alleles at a locus that consists of the less frequent allele. This number does not take genotype into account.

Effect size

The increase in risk (or proportion of population variation) that is conferred by a given causal variant.

Heritability

The proportion of phenotypic variation in a trait that is due to underlying genetic variation. In studies of humans, this value is usually calculated by comparing trait correlations in individuals of varying degrees of relatedness.

Mendelian disease

A disease that is carried in families in either a dominant or recessive manner and that is typically controlled by variants of large effect in a single gene.

Imputation

Based on the known linkage disequilibrium structure in fully genotyped individuals, the genotype of untyped variants can be inferred in individuals who are genotyped for a smaller number of variants.

Exome

The exome is the collection of known exons in our genome: this is the portion of the genome that is translated into proteins. As exons comprise only 1% of the genome and contain the most easily understood, functionally relevant information, sequencing of only the exome is a cheaper method of identifying most of the variants that are most likely to affect a trait.

Linkage disequilibrium

A nonrandom association between alleles at different loci.

Endophenotype

An intermediate phenotype that is heritable and associated with a disease but is not itself a symptom of the disease. Although there is little evidence to support the theory, it has been argued that endophenotypes would be a more tractable target for genetic analysis than the relevant disease state itself.

Haploinsufficiency

This occurs when a diploid organism only has one copy of a gene and both copies are required for correct function. This is one way that a protein-truncating mutation can influence predisposition to a disease.

Haplotype

A combination of alleles that are inherited together.

1000 Genomes Project

An international research consortium that will sequence the genomes of 1,200 individuals of various ethnicities. Most individuals will be sequenced to low coverage, or in exons only. The goals are to catalogue human variation with minor allele frequencies of 1% or greater and to refine and optimize strategies for sequencing large numbers of genomes.

Coverage

The number of sequence reads that have alignments that overlap a certain position. Because current sequencing strategies produce random reads, resulting in an uneven distribution of reads across the genome, a high average coverage is required to assure that most bases in the genome are covered by multiple reads.

Indel

A small insertion or deletion of nucleotides. If it occurs in an exon and is not a multiple of three in length, it results in a frameshift and usually the loss of gene function.

Splice-site variant

A variant, usually found at the intron–exon boundary, that alters the splicing of an exon to its surrounding exons.

Non-synonymous variant

A genetic variant that changes a codon for one amino acid to another amino acid. Many non-synonymous variants are well-tolerated, but others can cause a disease.

Co-segregation

In the pedigree of a family with a condition, the segregation pattern shows how often the putative causal variant is found to coincide with the condition. When a variant coincides with the condition in a family, the condition and the variant are said to co-segregate.

Compound heterozygote

When an individual inherits two different recessive mutations, one from each parent, in the same gene that cause the same phenotype. An example would be a single-nucleotide variant causing a codon for an amino acid to be changed into a stop codon in one allele and a 4-bp deletion in the other allele: each of these variants knock out their respective allele, resulting in neither copy functioning.

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Cirulli, E., Goldstein, D. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11, 415–425 (2010). https://doi.org/10.1038/nrg2779

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