Mapping heritability of obesity by brain cell types, bioRxiv, 2020-01-28
The underlying cell types mediating predisposition to obesity remain largely obscure. Here we first integrated recently published single-cell RNA-sequencing (scRNA-seq) data from >380 peripheral and nervous system cell types spanning 19 mouse organs with body mass index (BMI) genome-wide association study (GWAS) data from >450,000 individuals. Leveraging a novel strategy for integrating scRNA-seq data with GWAS data, we identified 22, exclusively neuronal, cell types from the subthalamus, midbrain, hippocampus, thalamus, cortex, pons, medulla, pallidum that were significantly enriched for BMI heritability (P<1.6×10-4). Using genes harboring coding mutations leading to syndromic forms of obesity, we replicate four midbrain cell types from the anterior pretectal nucleus, superior nucleus, periaqueductal gray and pallidum (P<1.7×10-4). Testing an additional set of 347 hypothalamic cell types, ventromedial hypothalamic steroidogenic-factor 1 (SF1) and cholecystokinin b receptor (CCKBR)-expressing neurons (P=4.9×10-5) previously implicated in energy homeostasis and glucose control and three cell types from the preoptic area of the hypothalamus and the lateral hypothalamus enriched for BMI GWAS associations (P<4.9×10-5). Together, our results suggest brain nuclei regulating integration of sensory stimuli, learning and memory are likely to play a key role in obesity and provide testable hypotheses for mechanistic follow-up studies.
biorxiv genetics 0-100-users 2020Fine-scale genomic analyses of admixed individuals reveal unrecognized genetic ancestry components in Argentina Native American, African and European genetic ancestries in Argentina, bioRxiv, 2020-01-25
AbstractWe are at the dawn of the efforts to describe and understand the origins of genetic diversity in Argentina from high-throughput data. This knowledge is a primary step in the intent of deciphering the specific genetic bases of diseases and drug response in the country. Similarly to other populations across the Americas, genetic ancestry in Argentinean populations traces back into African, European and Native American ancestors, reflecting a complex demographic history with multiple migration and admixture events in pre- and post-colonial times. However, little is known about the sub-continental origins of these three main ancestries. We present new high-throughput genotyping data for 87 admixed individuals across Argentina. This data was combined to previously published data for admixed individuals in the region and then compared to different reference panels specifically built to run population structure analyses at a sub-continental level. Concerning the European and African ancestries, we confirmed previous results about their main origins, and we provide new insights into the presence of other origins that reflect historical records. As for the Native American ancestry, leveraging genotype data for archaeological samples in the region in order to gain temporal depth in our analyses, we could identify four Native American components segregating in modern Argentinean populations. Three of them are also found in modern South American populations and are specifically represented in Central ChilePatagonia, Lowlands and Central Andes geographic areas. The fourth one may be specific to the Central Western region of Argentina.Identifying such component has not been straightforward since it is not well represented in any genomic data from the literature. Altogether, we provide useful insights into the multiple population groups from different continents that have contributed to present-days genetic diversity in Argentina. We encourage the generation of massive genotype data locally to further describe the genetic structure in Argentina.Author SummaryThe human genetic diversity in Argentina reflects demographic mechanisms during which the European colonists invaded a territory where Native American populations were settled. During colonial period, the slave trade also prompted many African people to move to Argentina. Little is known about the origins of the Native American and African components in Argentinean populations nowadays.Genotyping data for 87 admixed individuals throughout Argentina was generated and data from the literature was re-analyzed to shed light on this question. We confirmed that most of the European genetic ancestry comes from the South, although several individuals are related to Northern Europeans. We found that African origins in Argentina trace back from different regions. As for the Native American ancestry, we identified that it can be divided into four main components that correspond to Central ChilePatagonia, Lowlands, Central Andes and Central Western region of Argentina. In order to understand the specificity of the genetic diversity in Argentina, we should not rely on knowledge generated in other populations. Instead, more effort is required to generate specific massive genomic knowledge at the local level.
biorxiv genetics 0-100-users 2020Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations, bioRxiv, 2020-01-19
SUMMARYMost loci identified by GWAS have been found in populations of European ancestry (EA). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EA individuals, we identified 5,552 trait-variant associations at P<5×10−9, including 71 novel loci not found in EA populations. We also identified novel ancestry-specific variants not found in EA, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional, and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EA-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations, and compared genetic architecture and the impact of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.
biorxiv genetics 100-200-users 2020Investigating the Genetic Architecture of Non-Cognitive Skills Using GWAS-by-Subtraction, bioRxiv, 2020-01-16
AbstractEducational attainment (EA) is influenced by cognitive abilities and by other characteristics and traits. However little is known about the genetic architecture of these “non-cognitive” contributions to EA. Here, we use Genomic Structural Equation Modelling and results of prior genome-wide association studies (GWASs) of EA (N = 1,131,881) and cognitive test performance (N = 257,841) to estimate SNP associations with variation in EA that is independent of cognitive ability. We identified 157 genome-wide significant loci and a polygenic architecture accounting for 57% of genetic variance in EA. Phenotypic and biological annotation revealed that (1) both cognitive and non-cognitive contributions to EA were genetically correlated with socioeconomic success and longevity; and (2) non-cognitive contributions to EA were related to personality, decision making, risk-behavior, and increased risk for psychiatric disorders; (3) non-cognitive and cognitive contributions to EA were enriched in the same tissues and cell types, but (4) showed different associations with gray-matter neuroimaging phenotypes.
biorxiv genetics 100-200-users 2020Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations, bioRxiv, 2020-01-16
AbstractPolygenic scores (PGS) have been widely used to predict complex traits and risk of diseases using variants identified from genome-wide association studies (GWASs). To date, most GWASs have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European populations. Here, we develop a new theory to predict the relative accuracy (RA, relative to the accuracy in populations of the same ancestry as the discovery population) of PGS across ancestries. We used simulations and real data from the UK Biobank to evaluate our results. We found across various simulation scenarios that the RA of PGS based on trait-associated SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of SNP effect sizes and heritability. Altogether, we find that LD and MAF differences between ancestries explain alone up to ~70% of the loss of RA using European-based PGS in African ancestry for traits like body mass index and height. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWASs are mostly shared across continents.
biorxiv genetics 0-100-users 2020Recent fluctuations in Mexican American genomes have altered the genetic architecture of biomedical traits, bioRxiv, 2020-01-15
AbstractHispanicsLatinos are a diverse group of admixed populations with African, European, and Native American ancestries. They remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genome-wide genotype data from the Hispanic Community Health StudyStudy of Latinos, we find that Native American ancestry has increased over time across HispanicLatino populations, particularly in Mexican Americans where Native American ancestry increased by an average of ∼20% over the 50-year period spanning 1940s-1990s. We find similar patterns across American cities, and replicate our observations in an independent sample of Mexican Americans. These dynamic ancestry patterns are a result of a complex interaction of several population and cultural factors, including strong ancestry-related assortative mating and subtle shifts in migration with differences in subcontinental Native American ancestry over time. These factors have shaped patterns of genetic variation, including an increase in runs of homozygosity in Native American ancestral tracts, and also influenced the genetic architecture of complex traits within the Mexican American population. We show for height, a trait correlated with ancestry, polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within HispanicsLatinos that may influence biomedical traits, demonstrating a crucial need to improve our understanding of the genetic diversity of admixed populations.
biorxiv genetics 0-100-users 2020