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Concept: English American

215

Background For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient’s relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. Methods Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. Results Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. Conclusions The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).

Concepts: Genetics, United States, Sequence, Hypertrophic cardiomyopathy, White American, African American, European American, English American

103

We present a comprehensive assessment of genomic diversity in the African-American population by studying three genotyped cohorts comprising 3,726 African-Americans from across the United States that provide a representative description of the population across all US states and socioeconomic status. An estimated 82.1% of ancestors to African-Americans lived in Africa prior to the advent of transatlantic travel, 16.7% in Europe, and 1.2% in the Americas, with increased African ancestry in the southern United States compared to the North and West. Combining demographic models of ancestry and those of relatedness suggests that admixture occurred predominantly in the South prior to the Civil War and that ancestry-biased migration is responsible for regional differences in ancestry. We find that recent migrations also caused a strong increase in genetic relatedness among geographically distant African-Americans. Long-range relatedness among African-Americans and between African-Americans and European-Americans thus track north- and west-bound migration routes followed during the Great Migration of the twentieth century. By contrast, short-range relatedness patterns suggest comparable mobility of ∼15-16km per generation for African-Americans and European-Americans, as estimated using a novel analytical model of isolation-by-distance.

Concepts: United States, White American, African American, Native Americans in the United States, Southern United States, Texas, American Civil War, English American

56

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Concepts: Better, Gene, Genetics, Obesity, Body mass index, Genome-wide association study, Genetic linkage, English American

45

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans (brought largely by the trans-Atlantic slave trade), shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry.

Concepts: United States, Race, Native Americans in the United States, North America, Caribbean, American Civil War, European American, English American

38

Neuroimaging research in adults has consistently found that differential perception of race is associated with increased amygdala activity. We hypothesized that such neural biases unlikely reflect innate processes but instead emerge over development. In the current study, we used fMRI to examine the neurodevelopmental trajectory of the amygdala in response to race across childhood and adolescence ranging from 4 to 16 years. Thirty-two youths viewed African American and European American faces during a functional brain scan. Results suggest that differential amygdala response to African American faces does not emerge until adolescence, reflecting the increasing salience of race across development. In addition, greater peer diversity was associated with attenuated amygdala response to African American faces, suggesting that intergroup racial contact may reduce the salience of race.

Concepts: Neuroimaging, Black people, Neuroscience, Race, White American, Racism, European American, English American

37

The accurate description of ancestry is essential to interpret, access, and integrate human genomics data, and to ensure that these benefit individuals from all ancestral backgrounds. However, there are no established guidelines for the representation of ancestry information. Here we describe a framework for the accurate and standardized description of sample ancestry, and validate it by application to the NHGRI-EBI GWAS Catalog. We confirm known biases and gaps in diversity, and find that African and Hispanic or Latin American ancestry populations contribute a disproportionately high number of associations. It is our hope that widespread adoption of this framework will lead to improved analysis, interpretation, and integration of human genomics data.

Concepts: United States, Demographics of the United States, Spanish language, Interpretation, Latin America, European American, English American, Ancestor

29

This study used cross-lagged modeling to examine reciprocal relations between maternal and paternal harsh verbal discipline and adolescents' conduct problems and depressive symptoms. Data were from a sample of 976 two-parent families and their children (51% males; 54% European American, 40% African American). Mothers' and fathers' harsh verbal discipline at age 13 predicted an increase in adolescent conduct problems and depressive symptoms between ages 13 and 14. A child effect was also present, with adolescent misconduct at age 13 predicting increases in mothers' and fathers' harsh verbal discipline between ages 13 and 14. Furthermore, maternal and paternal warmth did not moderate the longitudinal associations between mothers' and fathers' use of harsh verbal discipline and adolescent conduct problems and depressive symptoms.

Concepts: Future, Race, White American, Mother, Father, European American, English American, Paternal bond

24

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into 7 major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. PC and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed considering only non-adjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3,741 genetically-identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2,018 genetically-identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to inter-marriage. The parent-child pairs revealed a trend towards increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories, creates interesting challenges and future opportunities for genetic epidemiologic studies.

Concepts: Genetics, Health, Epidemiology, Biology, United States, Kaiser Permanente, Native Americans in the United States, English American

21

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history and will help to facilitate the development of new approaches for disease-gene discovery. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth, notable for an excess of rare genetic variants, suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European American and African American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that approximately 73% of all protein-coding SNVs and approximately 86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs than other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the Out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, show the profound effect of recent human history on the burden of deleterious SNVs segregating in contemporary populations, and provide important practical information that can be used to prioritize variants in disease-gene discovery.

Concepts: DNA, Genetics, Natural selection, Evolution, Race, White American, European American, English American

20

Non-medical prescription opioid (NMPO) use is a substantial public health problem in the United States, with 1.5 million new initiates annually. Only 746,000 people received treatment for NMPO use in 2013, demonstrating substantial disparities in access to treatment. This study aimed to assess correlates of accessing substance use treatment among young adult NMPO users in Rhode Island, a state heavily impacted by NMPO use and opioid overdose.

Concepts: United States, United States Constitution, U.S. state, North Carolina, Massachusetts, New England, American Civil War, English American