Biology subjects

Sang Hong Lee

Publications and source records attributed to Sang Hong Lee.

9 recordsLinked to original sources

bioRxiv2016

A better design for stratified medicine based on genomic prediction

Genomic prediction shows promise for personalised medicine in which diagnosis and treatment are tailored to individuals based on their genetic profiles. Genomic prediction is arguably the greatest need for complex diseases and disorders for which both genetic and non-genetic factors contribute to risk. However, we have no adequate insight of the accuracy of such predictions, and how accuracy may vary between individuals or between populations. In this study, we present a theoretical framework to demonstrate that prediction accuracy can be maximised by targeting more informative individuals in a discovery set with closer relationships with the subjects, making prediction more similar to those in populations with small effective size (Ne). Increase of prediction accuracy from closer relationships is achieved under an additive model and does not rely on any interaction effects (gene x gene, gene x environment or gene x family). Using theory, simulations and real data analyses, we show that the predictive accuracy or the area under the receiver operating characteristic curve (AUC) increased exponentially with decreasing Ne. For example, with a set of realistic parameters (the sample size of discovery set N=3000 and heritability h2=0.5), AUC value approached to 0.9 (Ne=100) from 0.6 (Ne=10000), and the top percentile of the estimated genetic profile scores had 23 times higher proportion of cases than the general population (with Ne=100), which increased from 2 times higher proportion of cases (with Ne=10000). This suggests that different interventions in the top percentile risk groups maybe justified (i.e. stratified medicine). In conclusion, it is argued that there is considerable room to increase prediction accuracy for polygenic traits by using an efficient design of a smaller Ne (e.g. a design consisting of closer relationships) so that genomic prediction can be more beneficial in clinical applications in the near future.

Genetics↗

bioRxiv2016

Subtle stratification confounds estimates of heritability from rare variants

Genome-wide significant associations generally explain only a small proportion of the narrow-sense heritability of complex disease (h2). While considerably more heritability is explained by all genotyped SNPs (hg2), for most traits, much heritability remains missing (hg2 < h2). Rare variants, poorly tagged by genotyped SNPs, are a major potential source of the gap between hg2 and h2. Recent efforts to assess the contribution of both sequenced and imputed rare variants to phenotypes suggest that substantial heritability may lie in these variants. Here we analyze sequenced SNPs, imputed SNPs and haploSNPs-- haplotype variants constructed from within a sample, without using a reference panel-- and show that studies of heritability from these variants may be strongly confounded by subtle population stratification. For example, when meta-analyzing heritability estimates from 22 randomly ascertained case-control traits from the GERA cohort, we observe a statistically significant increase in heritability explained by imputed SNPs even after correcting for principal components (PCs) from genotyped (or imputed) SNPs. However, this increase is eliminated when correcting for stratification using PCs from a larger number of haploSNPs. We note that subtle stratification may also impact estimates of heritability from array SNPs, although we find that this is generally a less severe problem. Overall, our results suggest that estimating the heritability explained by rare variants for case-control traits requires exquisite control for population stratification, but current methods may not provide this level of control.

Genetics↗

bioRxiv2016

Commentary on "Limitations of GCTA as a solution to the missing heritability problem"

In a recent publication entitled \"Limitations of GCTA as a solution to the missing heritability problem\" Krishna Kumar et al. (2015 PNAS) claim that \"GCTA applied to current SNP data cannot produce reliable or stable estimates of heritability\". Here we show that those claims are false and that results presented by Krishna Kumar et al. are in fact entirely consistent with and can be predicted from the theory underlying GCTA.

Genetics↗

bioRxiv2015

Across-cohort QC analyses of genome-wide association study summary statistics from complex traits

Genome-wide association studies (GWASs) have been successful in discovering replicable SNP-trait associations for many quantitative traits and common diseases in humans. Typically the effect sizes of SNP alleles are very small and this has led to large genome-wide association meta-analyses (GWAMA) to maximize statistical power. A trend towards ever-larger GWAMA is likely to continue, yet dealing with summary statistics from hundreds of cohorts increases logistical and quality control problems, including unknown sample overlap, and these can lead to both false positive and false negative findings. In this study we propose a new set of metrics and visualization tools for GWAMA, using summary statistics from cohort-level GWASs. We proposed a pair of methods in examining the concordance between demographic information and summary statistics. In method I, we use the population genetics Fst statistic to verify the genetic origin of each cohort and their geographic location, and demonstrate using GWAMA data from the GIANT Consortium that geographic locations of cohorts can be recovered and outlier cohorts can be detected. In method II, we conduct principal component analysis based on reported allele frequencies, and is able to recover the ancestral information for each cohort. In addition, we propose a new statistic that uses the reported allelic effect sizes and their standard errors to identify significant sample overlap or heterogeneity between pairs of cohorts. Finally, to quantify unknown sample overlap across all pairs of cohorts we propose a method that uses randomly generated genetic predictors that does not require the sharing of individual-level genotype data and does not breach individual privacy.

Genetics↗

bioRxiv2015

MTG2: An efficient algorithm for multivariate linear mixed model analysis based on genomic information

We have developed an algorithm for genetic analysis of complex traits using genome-wide SNPs in a linear mixed model framework. Compared to current standard REML software based on the mixed model equation, our method could be more than 1000 times faster. The advantage is largest when there is only a single genetic covariance structure. The method is particularly useful for multivariate analysis, including multitrait models and random regression models for studying reaction norms. We applied our proposed method to publicly available mice and human data and discuss advantages and limitations.\n\nAvailability: MTG2 is available in https://sites.google.com/site/honglee0707/mtg2.\n\nContact: hong.lee@une.edu.au\n\nSupplementary information: Supplementary data are available.

Genetics↗

bioRxiv2015

Implications of simplified linkage equilibrium SNP simulation

In a recent paper published in PNAS (Golan et al. 2014)1, residual maximum likelihood (REML) seriously underestimated genetic variance explained by genome-wide single nucleotide polymorphism when using a case-control design. It was concluded that Haseman-Elston regression (denoted as PCGC in their paper) should be used instead of REML. Their conclusions were based on results from simplified linkage equilibrium SNP simulation (SLES), which the authors acknowledged may be unrealistic. We found that their simulation, SLES, unrealistically inflated the correlation between the eigenvectors of the genomic relationship matrix and disease status to values that are rarely observed in real data analyses. With a more realistic simulation that the authors failed to carry out (as they noted in their paper), we showed that there was no such inflated correlation between the eigenvectors of the genomic relationship matrix and disease status. Because REML uses the eigensystem of covariance structure, the inflated correlation artefactually constrained its estimates. We compared SNP-heritabilities from SLES and a more realistic simulation, showing that there was a substantial difference between the REML estimates from the two simulation strategies. Finally, we presented that there was no difference between REML and PCGC in real data analyses. This pattern from real data results differed strikingly from the pattern in the simulation study of Golan et al.1. One needs to be cautious of results drawn from SLES.

Genetics↗

bioRxiv2015

EigenGWAS: finding loci under selection through genome-wide association studies of eigenvectors in structured populations

We apply the statistical framework for genome-wide association studies (GWAS) to eigenvector decomposition (EigenGWAS), which is commonly used in population genetics to characterise the structure of genetic data. The approach does not require discrete sub-populations and thus it can be utilized in any genetic data where the underlying population structure is unknown, or where the interest is assessing divergence along a gradient. Through theory and simulation study we show that our approach can identify regions under selection along gradients of ancestry. In real data, we confirm this by demonstrating LCT to be under selection between HapMap CEU-TSI cohorts, and validated this selection signal across European countries in the POPRES samples. HERC2 was also found to be differentiated between both the CEU-TSI cohort and within the POPRES sample, reflecting the likely anthropological differences in skin and hair colour between northern and southern European populations. Controlling for population stratification is of great importance in any quantitative genetic study and our approach also provides a simple, fast, and accurate way of predicting principal components in independent samples. With ever increasing sample sizes across many fields, this approach is likely to be greatly utilized to gain individual-level eigenvectors avoiding the computational challenges associated with conducting singular value decomposition in large datasets. We have developed freely available software to facilitate the application of the methods.

Genetics↗

bioRxiv2015

Haplotypes of common SNPs can explain missing heritability of complex diseases

While genome-wide significant associations generally explain only a small proportion of the narrow-sense heritability of complex disease (h2), recent work has shown that more heritability is explained by all genotyped SNPs (hg2). However, much of the heritability is still missing (hg2 < h2). For example, for schizophrenia, h2 is estimated at 0.7-0.8 but hg2 is estimated at [~]0.3. Efforts at increasing coverage through accurately imputed variants have yielded only small increases in the heritability explained, and poorly imputed variants can lead to assay artifacts for case-control traits. We propose to estimate the heritability explained by a set of haplotype variants (haploSNPs) constructed directly from the study sample (hhap2). Our method constructs a set of haplotypes from phased genotypes by extending shared haplotypes subject to the 4-gamete test. In a large schizophrenia data set (PGC2-SCZ), haploSNPs with MAF > 0.1% explained substantially more phenotypic variance (hhap2 = 0.64 (S.E. 0.084)) than genotyped SNPs alone (hg2 = 0.32 (S.E. 0.029)). These estimates were based on cross-cohort comparisons, ensuring that cohort-specific assay artifacts did not contribute to our estimates. In a large multiple sclerosis data set (WTCCC2-MS), we observed an even larger difference between hhap2 and hg2, though data from other cohorts will be required to validate this result. Overall, our results suggest that haplotypes of common SNPs can explain a large fraction of missing heritability of complex disease, shedding light on genetic architecture and informing disease mapping strategies.

Genetics↗

bioRxiv2015

Contrasting regional architectures of schizophrenia and other complex diseases using fast variance components analysis

Heritability analyses of GWAS cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here, we analyze the genetic architecture of schizophrenia in 49,806 samples from the PGC, and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which [≥]71% of 1Mb genomic regions harbor at least one variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) among several pairs of GERA diseases; genetic correlations were on average 1.3x stronger than correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multi-component, multi-trait variance components analysis that overcomes prior computational barriers that made such analyses intractable at this scale.

Genetics↗