Comparing low-pass sequencing and genotyping for trait mapping in pharmacogenetics.

BACKGROUND: Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger. RESULTS: To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r2. Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r2 from the genotyping array was 0.90, which was comparable to the imputation r2 from 0.4x coverage sequencing, while the mean imputation r2 from 1x sequencing data was 0.96. CONCLUSIONS: These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.

Low-pass sequencing increases the power of GWAS and decreases measurement error of polygenic risk scores compared to genotyping arrays.

Low-pass sequencing (sequencing a genome to an average depth less than 1× coverage) combined with genotype imputation has been proposed as an alternative to genotyping arrays for trait mapping and calculation of polygenic scores. To empirically assess the relative performance of these technologies for different applications, we performed low-pass sequencing (targeting coverage levels of 0.5× and 1×) and array genotyping (using the Illumina Global Screening Array [GSA]) on 120 DNA samples derived from African- and European-ancestry individuals that are part of the 1000 Genomes Project. We then imputed both the sequencing data and the genotyping array data to the 1000 Genomes Phase 3 haplotype reference panel using a leave-one-out design. We evaluated overall imputation accuracy from these different assays as well as overall power for GWAS from imputed data and computed polygenic risk scores for coronary artery disease and breast cancer using previously derived weights. We conclude that low-pass sequencing plus imputation, in addition to providing a substantial increase in statistical power for genome-wide association studies, provides increased accuracy for polygenic risk prediction at effective coverages of ∼0.5× and higher compared to the Illumina GSA.

Identifying genetic variants that affect viability in large cohorts.

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

Detection and interpretation of shared genetic influences on 42 human traits.

We performed a scan for genetic variants associated with multiple phenotypes by comparing large genome-wide association studies (GWAS) of 42 traits or diseases. We identified 341 loci (at a false discovery rate of 10%) associated with multiple traits. Several loci are associated with multiple phenotypes; for example, a nonsynonymous variant in the zinc transporter SLC39A8 influences seven of the traits, including risk of schizophrenia (rs13107325: log-transformed odds ratio (log OR) = 0.15, P = 2 × 10(-12)) and Parkinson disease (log OR = -0.15, P = 1.6 × 10(-7)), among others. Second, we used these loci to identify traits that have multiple genetic causes in common. For example, variants associated with increased risk of schizophrenia also tended to be associated with increased risk of inflammatory bowel disease. Finally, we developed a method to identify pairs of traits that show evidence of a causal relationship. For example, we show evidence that increased body mass index causally increases triglyceride levels.

Approximately independent linkage disequilibrium blocks in human populations.

UNLABELLED: We present a method to identify approximately independent blocks of linkage disequilibrium in the human genome. These blocks enable automated analysis of multiple genome-wide association studies. AVAILABILITY AND IMPLEMENTATION: code: http://bitbucket.org/nygcresearch/ldetect; data: http://bitbucket.org/nygcresearch/ldetect-data. CONTACT: tberisa@nygenome.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.