Tumor mutational load predicts survival after immunotherapy across multiple cancer types, Nature Genetics, 2019-01-08
Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
nature genetics genetics 500+-users 2019Estimating heritability of complex traits in admixed populations with summary statistics, bioRxiv, 2018-12-21
AbstractAll summary statistics-based methods to estimate the heritability of SNPs (hg2) rely on accurate linkage disequilibrium (LD) calculations. In admixed populations, such as African Americans and Latinos, LD estimates are influenced by admixture and can result in biased hg2 estimates. Here, we introduce covariate-adjusted LD score regression (cov-LDSC), a method to provide robust hg2 estimates from GWAS summary statistics and in-sample LD estimates in admixed populations. In simulations, we observed that unadjusted LDSC underestimates hg2 by 10%-60%; in contrast, cov-LDSC is robust to all simulation parameters. We applied cov-LDSC to approximately 170,000 Latino, 47,000 African American 135,000 European individuals in three quantitative and five dichotomous phenotypes. Our results show that most traits have high concordance of hg2 between ethnic groups; for example in the 23andMe cohort, estimates of hg2 for BMI are 0.22 ± 0.01, 0.23 ± 0.03 and 0.22 ± 0.01 in Latino, African American and European populations respectively. However, for age at menarche, we observe population specific heritability differences with estimates of hg2 of 0.10 ± 0.03, 0.33 ± 0.13 and 0.19 ± 0.01 in Latino, African American and European populations respectively.
biorxiv genetics 100-200-users 2018Using DNA from mothers and children to study parental investment in children's educational attainment, bioRxiv, 2018-12-10
This study tested implications of new genetic discoveries for understanding the association between parental investment and children's educational attainment. A novel design matched genetic data from 860 British mothers and their children with home-visit measures of parenting the E-Risk Study. Three findings emerged. First, both mothers' and children's education-associated genetics, summarized in a genome-wide polygenic score, predicted parenting -- a gene-environment correlation. Second, accounting for genetic influences slightly reduced associations between parenting and children's attainment -- indicating some genetic confounding. Third, mothers' genetics influenced children's attainment over and above genetic mother-to-child transmission, via cognitively-stimulating parenting -- an environmentally-mediated effect. Findings imply that, when interpreting parents' effects on children, environmentalists must consider genetic transmission, but geneticists must also consider environmental transmission.
biorxiv genetics 100-200-users 2018Models of archaic admixture and recent history from two-locus statistics, bioRxiv, 2018-12-08
AbstractWe learn about population history and underlying evolutionary biology through patterns of genetic polymorphism. Many approaches to reconstruct evolutionary histories focus on a limited number of informative statistics describing distributions of allele frequencies or patterns of linkage disequilibrium. We show that many commonly used statistics are part of a broad family of two-locus moments whose expectation can be computed jointly and rapidly under a wide range of scenarios, including complex multi-population demographies with continuous migration and admixture events. A full inspection of these statistics reveals that widely used models of human history fail to predict simple patterns of linkage disequilibrium. To jointly capture the information contained in classical and novel statistics, we implemented a tractable likelihood-based inference framework for demographic history. Using this approach, we show that human evolutionary models that include archaic admixture in Africa, Asia, and Europe provide a much better description of patterns of genetic diversity across the human genome. We estimate that an unidentified, deeply diverged population admixed with modern humans within Africa both before and after the split of African and Eurasian populations, contributing 4 - 8% genetic ancestry to individuals in world-wide populations.Author SummaryThroughout human history, populations have expanded and contracted, split and merged, and ex-changed migrants. Because these events affected genetic diversity, we can learn about human history by comparing predictions from evolutionary models to genetic data. Here, we show how to rapidly compute such predictions for a wide range of diversity measures within and across populations under complex demographic scenarios. While widely used models of human history accurately predict common measures of diversity, we show that they strongly underestimate the co-occurence of low frequency mutations within human populations in Asia, Europe, and Africa. Models allowing for archaic admixture, the relatively recent mixing of human populations with deeply diverged human lineages, resolve this discrepancy. We use such models to infer demographic models that include both recent and ancient features of human history. We recover the well-characterized admixture of Neanderthals in Eurasian populations, as well as admixture from an as-yet unknown diverged human population within Africa, further suggesting that admixture with deeply diverged lineages occurred multiple times in human history. By simultaneously testing model predictions for a broad range of diversity statistics, we can assess the robustness of common evolutionary models, identify missing historical events, and build more informed models of human demography.
biorxiv genetics 100-200-users 2018