Dataset Information

Beyond missing heritability: prediction of complex traits.

ABSTRACT: Despite rapid advances in genomic technology, our ability to account for phenotypic variation using genetic information remains limited for many traits. This has unfortunately resulted in limited application of genetic data towards preventive and personalized medicine, one of the primary impetuses of genome-wide association studies. Recently, a large proportion of the "missing heritability" for human height was statistically explained by modeling thousands of single nucleotide polymorphisms concurrently. However, it is currently unclear how gains in explained genetic variance will translate to the prediction of yet-to-be observed phenotypes. Using data from the Framingham Heart Study, we explore the genomic prediction of human height in training and validation samples while varying the statistical approach used, the number of SNPs included in the model, the validation scheme, and the number of subjects used to train the model. In our training datasets, we are able to explain a large proportion of the variation in height (h(2) up to 0.83, R(2) up to 0.96). However, the proportion of variance accounted for in validation samples is much smaller (ranging from 0.15 to 0.36 depending on the degree of familial information used in the training dataset). While such R(2) values vastly exceed what has been previously reported using a reduced number of pre-selected markers (<0.10), given the heritability of the trait (? 0.80), substantial room for improvement remains.

SUBMITTER: Makowsky R

PROVIDER: S-EPMC3084207 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Beyond missing heritability: prediction of complex traits.

Makowsky Robert R Pajewski Nicholas M NM Klimentidis Yann C YC Vazquez Ana I AI Duarte Christine W CW Allison David B DB de los Campos Gustavo G

PLoS genetics 20110428 4

Despite rapid advances in genomic technology, our ability to account for phenotypic variation using genetic information remains limited for many traits. This has unfortunately resulted in limited application of genetic data towards preventive and personalized medicine, one of the primary impetuses of genome-wide association studies. Recently, a large proportion of the "missing heritability" for human height was statistically explained by modeling thousands of single nucleotide polymorphisms conc ...[more]

PMID: 21552331

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Project description:The proportion of genetic variation in complex traits explained by rare variants is a key question for genomic prediction, and for identifying the basis of "missing heritability"--the proportion of additive genetic variation not captured by common variants on SNP arrays. Sequence variants in transcript and regulatory regions from 429 sequenced animals were used to impute high density SNP genotypes of 3311 Holstein sires to sequence. There were 675,062 common variants (MAF>0.05), 102,549 uncommon variants (0.01<MAF<0.05), and 83,856 rare variants (MAF<0.01). We describe a novel method for estimating the proportion of the rare variants that are sequencing errors using parent-progeny duos. We then used mixed model methodology to estimate the proportion of variance captured by these different classes of variants for fat, milk and protein yields, as well as for fertility. Common sequence variants captured 83%, 77%, 76% and 84% of the total genetic variance for fat, milk, and protein yields and fertility, respectively. This was between 2 and 5% more variance than that captured from 600k SNPs on a high density chip, although the difference was not significant. Rare variants captured 3%, 0%, 1% and 14% of the genetic variance for fat, milk and protein yields, and fertility respectively, whereas pedigree explained the remaining amount of genetic variance (none for fertility). The proportion of variation explained by rare variants is likely to be under-estimated due to reduced accuracies of imputation for this class of variants. Using common sequence variants slightly improved accuracy of genomic predictions for fat and milk yield, compared to high density SNP array genotypes. However, including rare variants from transcript regions did not increase the accuracy of genomic predictions. These results suggest that rare variants recover a small percentage of the missing heritability for complex traits, however very large reference sets will be required to exploit this to improve the accuracy of genomic predictions. Our results do suggest the contribution of rare variants to genetic variation may be greater for fitness traits.

Dataset Information

Beyond missing heritability: prediction of complex traits.

Publications

Beyond missing heritability: prediction of complex traits.

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