Evolutionary selection underlying the genetic architecture of complex traits Carolina Medina-Gomez Oscar Lao SNPs and Diseases Molecular School of Medicine Thursday, November 15 th , 2018
Ethnic differences in bone mineral density and fracture risk have been described • Finkelstein et al. 2002. JCEM. African American, Chinese, Japanese premenopausal women (SWAN, N~2,000). African Americans and Asians (after adjustment) have higher BMD than Caucasians • Marshall et al. 2008 JBMR. Black, Asian, Hispanic, Caucasians. Men over 65 years. (MrOS, N~3,300). Self reported ethnicity. Greater cortical thickness and trabecular vBMD in Blacks and Asians. • Kalkwarf et al. 2012. JBMR. Children 1-36 months. (CHOPs, N~307). No differences in LS BMD between Blacks and Whites. Blacks higher BMD at age >5 years.
Research questions (to start) 1. Are the reported ethnic differences in BMD variation already present at early ages? 2. If so, can we attribute these differences to genetic factors?
Generation R Study is a prospective multiethnic birth cohort of children followed to early adulthood Rotterdam 2010 Ongoing population-based • longitudinal study including 9,778 mothers followed since pregnancy (04/2002-01/2006) Parents coming from over 100 • different countries N~6,500. DXA measurements • average age of 6 years N~5,733 with GWAS • N~4,000 with GWAS & DXA • Generation R sample
Advantages of the Generation R multiethnic design Possible advantages of the Generation R setting: • Restricted geographical area • > Similar light exposition • < variation in diet and physical activity • = Health Care quality
Working Ethnicity Definition from questionnaires based on the Dutch Central Bureau of Statistics • The classification is based on the mother’s country of birth. If she is also born in the Netherlands, the background is determined by the father’s country of birth.
Country of birth might not be the best surrogate for ancestry in genetic studies
Using genetic data to assess ancestry is a well-known technique
Using genetic data (instead of questionnaire ) to assess ancestry GENERATION R GWAS POPULATION
Generation R ethnic groups show heterogeneous / scattered clustering when using genetic data Dutch Dutch Antilles Surinamense Indonesian African Capo Verdians American Western American non Western Morrocan Asians non Western Asians Western Turkish Europeans Oceanic In this Graph the pink corresponds to the Yoruba panel in the Hapmap while dark and light blue correspond to JPN and NE panels respectively.
Applying stringent criteria for ancestry definition is not possible ( ±4SD in PC1, PC2 HapMap cluster) Africans 31 Asians 36 Europeans 2921 Mix 2745
Genetic ancestry clustering algorithms should help overcoming biases generated by ethnicity definitions Admixture analysis: ancestry proportions and population allele frequencies Caucasian African Asian Mix
23&me most popular feature: Ancestry Analysis
Using admixture one can define 4 main clusters for a more powerful setting for analysis GENERATION R GWAS POPULATION
Differences in BMD according to ethnic background based on questionnaire data 6,126 children DXA and ethnicity information (15 ethnicities) Africans Suri_Creole Africans Antillans Europeans Oceanic Dutch Europeans Americans Turkish NorthAfricans* Asians Asians Suri_Hindu
Differences in BMD according to ethnic background based on genetic data After adjustment for age, gender, fat mass, lean mass and height EthnicGroup LSmean Difference Pval Asian 0.559 0.022 <2E-16 Caucasian 0.552 0.016 <2E-16 African 0.575 - - African Caucasian Asian *Additional cofounders: Maternal smoking, Maternal homocysteine level, Maternal marital status, Maternal weight, Maternal height, Infant birth weight, Child Breastfeeding, Child protein intake, Child sports. Diet questionnaires?
Within the Caucasians the BMD increases as the % of African ancestry increases
61/63 SNPs in GenR data SNP A1 A2 Ind #1 SCORE Ind #2 SCORE rs17482952 G A GG 2 GG 2 rs12407028 C T TT 0 CC 2 rs7521902 A C CA 1 CA 1 rs1346004 A G GG 0 GA 1 rs6426749 C G CG 1 CC 2 rs479336 G T GG 2 GG 2 rs4233949 C A AC 1 AC 1 1. Score 7 11 2. Score
The allele score is positively associated with BMD in children of the Generation R cohort • Score explains ~5% of phenotypic variance. 2.4% when corrected by PCs
By mendelian randomization similar distribution of score- bins for a particular covariate is expected accross bins Distribution of gender across the score bins • Male • Female
BMD-increasing alleles were more likely to have higher frequencies in African than in Caucasian participants Increasing Alleles Caucasian: 43 to 78 (60) Asian: 48 to 74 (59) African 50 to 78 (66) Quintiles BMD Highest (88) 0.72 SDs Lowest (53) 0.53 SDs The 61% of the African children are in the 2 highest quintiles (p < 1x10 -16 ) Estrada et al. 2012. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genetics. 44, 491–501
BMD-increasing alleles were more likely to have higher frequencies in African than in Caucasian participants Estrada et al. 2012. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genetics. 44, 491–501
Two pediatric studies confirmed that genetic variants associated with higher BMD are more common in Africans Higher BMD Higher BMD genetic variants genetic variants
Behavior of the BMD-increasing alleles support no stratification influencing the results • 30/61 is Minor Allele (based in the CEU freq). For 23 of them the difference is even higher than 10% favoring the African populations. The bar plots in the background represent the frequency of BMD-increasing alleles in HapMap CEU panel. Dots represent the difference in frequency between S. African and European
The Human Genome Diversity Panel as a replication source of our findings 1,063 cultured lymphoblastoid cell lines (LCLs) from 1,050 individuals in 52 world populations Genotype 650,000 SNPs
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Genetic differentiation CEPH-HGDP panel 939 samples 51 human populations of global distribution Li et al 2008 (Science) Carolina Medina-Gómez et al, 2015 (MBE)
Significant Differences in proportion of BMD increasing alleles is seen only in populations of African origin
Conclusions (1) • Genetic variants influencing BMD variation in NE-adults are predictive in children from different ethnicities. • Children of African descent have a higher frequency of BMD-increasing alleles than children of Asian and Caucasian descent, and these results cannot be attributed to stratification. • Analysis throughout worldwide populations show a similar spatial distribution of the associated variants as observed in the Generation R cohort. • Can BMD distributions today be explained by mechanisms of polygenic evolution (subtle allele frequencies shifts at many loci)?
HUMAN EVOLUTION Nielsen et al 2017
HUMAN EVOLUTION Adapted from Vattathil & Akey, 2015. Cell
CONSEQUENCES OF HUMAN BIOLOGICAL EVOLUTION (1) Simonti et al 2016 Sankararaman et al 2
HUMAN CULTURAL EVOLUTION https://es.pinterest.com/
CONSEQUENCES OF HUMAN BIOLOGICAL EVOLUTION (2) Fan et al 2016
CONSEQUENCES OF HUMAN BIOLOGICAL EVOLUTION (3) DISUSE
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Ruff et al 2015 Chirchir et al 2014 PNAS PNAS
EVOLUTION BMD IS A CASE OF DISUSE? 73% BMD increasing alleles actually constitute ancestral alleles Population Mean MAF P value compared to other GWAS SNPs 8.3*10 -3 CEU 0.3 CHB/JPT 0.26 0.13 YRI 0.21 0.83 Carolina Medina-Gómez et al, 2015 (MBE)
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Hypothesis one High BMD is the ancestral state Polygenic selection out of Africa towards lower BMD Hypothesis two Relaxation of selection in Africa so BMD alleles fluctuate at random compared to non-African populations Hypothesis three BMD decreasing alleles are introgressed from a non-Homo sapiens species
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Trend in ancient samples Pvalue 0.0006, R 2 0.109 Mathieson et al 2015 Nature
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Archaic samples
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Trend in ancient samples Population/species Mean BMD-GS Neanderthal 1.344 Denisova 1.345 Pan troglodytes 1.356 SubAfrica 1.131 NorthAfrica 1.027 MiddleEast 0.972 SouthAsia 0.987 Europe 0.984 EastAsia 1.029 Oceania 0.886 NativeAmerican 1.077
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? GS/Neanderthal trend R2 = 0.31; Pvalue = 0.023 Fu et al 2016 Nature
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Archaic introgression Sankararaman et al 2014 Na
CONSEQUENCES OF CULTURAL EVOLUTION BMD IS A CASE OF DISUSE? Archaic introgression Excluding rs10416218, for which Neanderthal shows the decreasing BMD allele
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