On rare variants in principal component analysis of population stratification
Abstract Background Population stratification is a known confounder of genome-wide association studies, as it can lead to false positive results. Principal component analysis (PCA) method is widely applied in the analysis of population structure with common variants. However, it is still unclear abo...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | BMC Genetics |
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| Online Access: | http://link.springer.com/article/10.1186/s12863-020-0833-x |
| _version_ | 1818149778682281984 |
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| author | Shengqing Ma Gang Shi |
| author_facet | Shengqing Ma Gang Shi |
| author_sort | Shengqing Ma |
| collection | DOAJ |
| description | Abstract Background Population stratification is a known confounder of genome-wide association studies, as it can lead to false positive results. Principal component analysis (PCA) method is widely applied in the analysis of population structure with common variants. However, it is still unclear about the analysis performance when rare variants are used. Results We derive a mathematical expectation of the genetic relationship matrix. Variance and covariance elements of the expected matrix depend explicitly on allele frequencies of the genetic markers used in the PCA analysis. We show that inter-population variance is solely contained in K principal components (PCs) and mostly in the largest K-1 PCs, where K is the number of populations in the samples. We propose FPC, ratio of the inter-population variance to the intra-population variance in the K population informative PCs, and d 2, sum of squared distances among populations, as measures of population divergence. We show analytically that when allele frequencies become small, the ratio FPC abates, the population distance d 2 decreases, and portion of variance explained by the K PCs diminishes. The results are validated in the analysis of the 1000 Genomes Project data. The ratio FPC is 93.85, population distance d 2 is 444.38, and variance explained by the largest five PCs is 17.09% when using with common variants with allele frequencies between 0.4 and 0.5. However, the ratio, distance and percentage decrease to 1.83, 17.83 and 0.74%, respectively, with rare variants of frequencies between 0.0001 and 0.01. Conclusions The PCA of population stratification performs worse with rare variants than with common ones. It is necessary to restrict the selection to only the common variants when analyzing population stratification with sequencing data. |
| first_indexed | 2024-12-11T13:12:27Z |
| format | Article |
| id | doaj.art-fbeef469ed9647c1a8486970db74ad70 |
| institution | Directory Open Access Journal |
| issn | 1471-2156 |
| language | English |
| last_indexed | 2024-12-11T13:12:27Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genetics |
| spelling | doaj.art-fbeef469ed9647c1a8486970db74ad702022-12-22T01:06:09ZengBMCBMC Genetics1471-21562020-03-0121111110.1186/s12863-020-0833-xOn rare variants in principal component analysis of population stratificationShengqing Ma0Gang Shi1State Key Laboratory of Integrated Services Networks, Xidian UniversityState Key Laboratory of Integrated Services Networks, Xidian UniversityAbstract Background Population stratification is a known confounder of genome-wide association studies, as it can lead to false positive results. Principal component analysis (PCA) method is widely applied in the analysis of population structure with common variants. However, it is still unclear about the analysis performance when rare variants are used. Results We derive a mathematical expectation of the genetic relationship matrix. Variance and covariance elements of the expected matrix depend explicitly on allele frequencies of the genetic markers used in the PCA analysis. We show that inter-population variance is solely contained in K principal components (PCs) and mostly in the largest K-1 PCs, where K is the number of populations in the samples. We propose FPC, ratio of the inter-population variance to the intra-population variance in the K population informative PCs, and d 2, sum of squared distances among populations, as measures of population divergence. We show analytically that when allele frequencies become small, the ratio FPC abates, the population distance d 2 decreases, and portion of variance explained by the K PCs diminishes. The results are validated in the analysis of the 1000 Genomes Project data. The ratio FPC is 93.85, population distance d 2 is 444.38, and variance explained by the largest five PCs is 17.09% when using with common variants with allele frequencies between 0.4 and 0.5. However, the ratio, distance and percentage decrease to 1.83, 17.83 and 0.74%, respectively, with rare variants of frequencies between 0.0001 and 0.01. Conclusions The PCA of population stratification performs worse with rare variants than with common ones. It is necessary to restrict the selection to only the common variants when analyzing population stratification with sequencing data.http://link.springer.com/article/10.1186/s12863-020-0833-xRare variantPopulation stratificationPrincipal component analysisSingle nucleotide polymorphism |
| spellingShingle | Shengqing Ma Gang Shi On rare variants in principal component analysis of population stratification BMC Genetics Rare variant Population stratification Principal component analysis Single nucleotide polymorphism |
| title | On rare variants in principal component analysis of population stratification |
| title_full | On rare variants in principal component analysis of population stratification |
| title_fullStr | On rare variants in principal component analysis of population stratification |
| title_full_unstemmed | On rare variants in principal component analysis of population stratification |
| title_short | On rare variants in principal component analysis of population stratification |
| title_sort | on rare variants in principal component analysis of population stratification |
| topic | Rare variant Population stratification Principal component analysis Single nucleotide polymorphism |
| url | http://link.springer.com/article/10.1186/s12863-020-0833-x |
| work_keys_str_mv | AT shengqingma onrarevariantsinprincipalcomponentanalysisofpopulationstratification AT gangshi onrarevariantsinprincipalcomponentanalysisofpopulationstratification |