Mixed Race Studies

Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort

Genetics
August 1, 2015, Volume 200, Number 4
pages 1285-1295
DOI: 10.1534/genetics.115.178616

Yambazi Banda
Mark N. Kvale
Thomas J. Hoffmann
Stephanie E. Hesselson
Dilrini Ranatunga
Hua Tang
Chiara Sabatti
Lisa A. Croen
Brad P. Dispensa
Mary Henderson
Carlos Iribarren
Eric Jorgenson
Lawrence H. Kushi
Dana Ludwig
Diane Olberg
Charles P. Quesenberry Jr.
Sarah Rowell
Marianne Sadler
Lori C. Sakoda
Stanley Sciortino
Ling Shen
David Smethurst
Carol P. Somkin
Stephen K. Van Den Eeden
Lawrence Walter
Rachel A. Whitmer
Pui-Yan Kwok
Catherine Schaefer
Neil Risch

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 Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven 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. Principal component (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 nonadjacent 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 3741 genetically identified parent–child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent–child pairs was largely due to intermarriage. The parent–child pairs revealed a trend toward 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.

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Characterizing the Admixed African Ancestry of African Americans

Genome Biology
Volume 10, Issue 12 (2009)
R141
DOI: 10.1186/gb-2009-10-12-r141

Fouad Zakharia
Department of Genetics
Stanford University School of Medicine

Analabha Basu
Institute for Human Genetics
University of California, San Francisco

Devin Absher
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama

Themistocles L. Assimes
Division of Cardiovascular Medicine
Stanford University School of Medicine

Alan S. Go
Division of Research
Kaiser Permanente, Oakland, California

Mark A. Hlatky
Department of Health, Research and Policy
Stanford University School of Medicine

Carlos Iribarren
Division of Research
Kaiser Permanente, Oakland, California

Joshua W. Knowles
Division of Cardiovascular Medicine
Stanford University School of Medicine

Jun Li
Department of Human Genetics
University of Michigan

Balasubramanian Narasimhan
Department of Health, Research and Policy
Stanford University School of Medicine

Steven Sidney
Division of Research
Kaiser Permanente, Oakland, California

Audrey Southwick
Department of Infectious Diseases
Stanford University School of Medicine

Richard M. Myers
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama

Thomas Quertermous
Division of Cardiovascular Medicine
Stanford University School of Medicine

Neil Risch
Institute for Human Genetics
University of California, San Francisco

Division of Research
Kaiser Permanente, Oakland, California

Department of Epidemiology and Biostatistics
University of California, San Francisco

Hua Tang
Department of Genetics
Stanford University School of Medicine

Background: Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.

Results: From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.

Conclusions: These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.

…Although much attention has been paid in the genetics literature to the continental admixture underlying the genetic makeup of African Americans, less attention has been paid to the within-continental contribution to African Americans, in particular from the continent of Africa. Studies have focused primarily on the matrilineally inherited mitochondrial DNA(mtDNA) and patrilineally inherited Y chromosome. These two DNA sources have gained wide prominence owing, in part, to their use by ancestry-testing companies to identify the regional and ethnic origins of their subscribers. Yet these two sources provide a very narrow perspective in delineating only two of possibly thousands of ancestral lineages in an individual.

The majority of African Americans derive their African ancestry from the approximately 500,000 to 650,000 Africans that were forcibly brought to British North America as slaves during the Middle Passage. These individuals were deported primarily from various geographic regions of Western Africa, ranging from Senegal to Nigeria to Angola. Thus, it has been estimated that the majority of African Americans derive ancestry from these geographic regions, although more central and eastern locations also have contributed.  Recent studies of African and African-American mtDNA haplotypes and autosomal microsatellite markers also confirmed a broad range of Western Africa as the likely roots of most African Americans…

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Categorization of humans in biomedical research: genes, race and disease

Genome Biology 2002
Volume 3, Number 7
2002-07-01
Print ISSN 1465-6906; Online ISSN 1465-6914
DOI: 10.1186/gb-2002-3-7-comment2007

Neil Risch
Department of Genetics
Stanford University School of Medicine, Stanford, California

Esteban Burchard
Department of Medicine
University of California, San Francisco, California

Elad Ziv
Department of Medicine
University of California, San Francisco, California

Hua Tang
Department of Statistics
Stanford University, Stanford, California

Opinion

A debate has arisen regarding the validity of racial/ethnic categories for biomedical and genetic research. Some claim ‘no biological basis for race’ while others advocate a ‘race-neutral’ approach, using genetic clustering rather than self-identified ethnicity for human genetic categorization. We provide an epidemiologic perspective on the issue of human categorization in biomedical and genetic research that strongly supports the continued use of self-identified race and ethnicity.

A major discussion has arisen recently regarding optimal strategies for categorizing humans, especially in the United States, for the purpose of biomedical research, both etiologic and pharmaceutical. Clearly it is important to know whether particular individuals within the population are more susceptible to particular diseases or most likely to benefit from certain therapeutic interventions. The focus of the dialogue has been the relative merit of the concept of ‘race’ or ‘ethnicity’, especially from the genetic perspective. For example, a recent editorial in the New England Journal of Medicine [1] claimed that “race is biologically meaningless” and warned that “instruction in medical genetics should emphasize the fallacy of race as a scientific concept and the dangers inherent in practicing race-based medicine.” In support of this perspective, a recent article in Nature Genetics [2] purported to find that “commonly used ethnic labels are both insufficient and inaccurate representations of inferred genetic clusters.” Furthermore, a supporting editorial in the same issue [3] concluded that “population clusters identified by genotype analysis seem to be more informative than those identified by skin color or self-declaration of ‘race’.” These conclusions seem consistent with the claim that “there is no biological basis for ‘race'” [3] and that “the myth of major genetic differences across ‘races’ is nonetheless worth dismissing with genetic evidence” [4]. Of course, the use of the term “major” leaves the door open for possible differences but a priori limits any potential significance of such differences.

In our view, much of this discussion does not derive from an objective scientific perspective. This is understandable, given both historic and current inequities based on perceived racial or ethnic identities, both in the US and around the world, and the resulting sensitivities in such debates. Nonetheless, we demonstrate here that from both an objective and scientific (genetic and epidemiologic) perspective there is great validity in racial/ethnic self-categorizations, both from the research and public policy points of view…

…Admixture and genetic categorization in the United States…

What are the implications of these census results and the admixture that has occurred in the US population for genetic categorization in biomedical research studies in the US? Gene flow from non-Caucasians into the US Caucasian population has been modest. On the other hand, gene flow from Caucasians into African Americans has been greater; several studies have estimated the proportion of Caucasian admixture in African Americans to be approximately 17%, ranging regionally from about 12% to 23% [22]. Thus, despite the admixture, African Americans remain a largely African group, reflecting primarily their African origins from a genetic perspective. Asians and Pacific Islanders have been less influenced by admixture and again closely represent their indigenous origins. The same is true for Native Americans, although some degree of Caucasian admixture has occurred in this group as well [23]…

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The Importance of Race and Ethnic Background in Biomedical Research and Clinical Practice

New England Journal of Medicine
2003-03-20
Volume 348, Number 12
pages 1170-1175

Esteban González Burchard, M.D.
Elad Ziv, M.D.
Natasha Coyle, Ph.D.
Scarlett Lin Gomez, Ph.D.
Hua Tang, Ph.D.
Andrew J. Karter, Ph.D.
Joanna L. Mountain, Ph.D.
Eliseo J. Pérez-Stable, M.D.
Dean Sheppard, M.D.
Neil Risch, Ph.D.

A debate has recently arisen over the use of racial classification in medicine and biomedical research. In particular, with the completion of a rough draft of the human genome, some have suggested that racial classification may not be useful for biomedical studies, since it reflects “a fairly small number of genes that describe appearance” and “there is no basis in the genetic code for race.” In part on the basis of these conclusions, some have argued for the exclusion of racial and ethnic classification from biomedical research. In the United States, race and ethnic background have been used as cause for discrimination, prejudice, marginalization, and even subjugation. Excessive focus on racial or ethnic differences runs the risk of undervaluing the great diversity that exists among persons within groups. However, this risk needs to be weighed against the fact that in epidemiologic and clinical research, racial and ethnic categories are useful for generating and exploring hypotheses about environmental and genetic risk factors, as well as interactions between risk factors, for important medical outcomes. Erecting barriers to the collection of information such as race and ethnic background may provide protection against the aforementioned risks; however, it will simultaneously retard progress in biomedical research and limit the effectiveness of clinical decision making.

Race and Ethnic Background as Geographic and Sociocultural Constructs with Biologic Ramifications

Definitions of race and ethnic background have often been applied inconsistently. The classification scheme used in the 2000 U.S. Census, which is often used in biomedical research, includes five major groups: black or African American, white, Asian, native Hawaiian or other Pacific Islander, and American Indian or Alaska native. In general, this classification scheme emphasizes the geographic region of origin of a person’s ancestry. Ethnic background is a broader construct that takes into consideration cultural tradition, common history, religion, and often a shared genetic heritage…

…Sociocultural Correlates of Race and Ethnic Background

The racial or ethnic groups described above do not differ from each other solely in terms of genetic makeup, especially in a multiracial and multicultural society such as the United States. Socioeconomic status is strongly correlated with race and ethnic background and is a robust predictor of access to and quality of health care and education, which, in turn, may be associated with differences in the incidence of diseases and the outcomes of those diseases. For example, black Americans with end-stage renal disease are referred for renal transplantation at lower rates than white Americans. Black Americans are also referred for cardiac catheterization less frequently than white Americans. In some cases, these differences may be due to bias on the part of physicians and discriminatory practices in medicine. Nonetheless, racial or ethnic differences in the outcomes of disease sometimes persist even when discrepancies in the use of interventions known to be beneficial are considered. For example, the rate of complications from type 2 diabetes mellitus varies according to racial or ethnic category among members of the same health maintenance organization, despite uniform utilization of outpatient services and after adjustment for levels of education and income, health behavior, and clinical characteristics. The evaluation of whether genetic (as well as nongenetic) differences underlie racial disparities is appropriate in cases in which important racial and ethnic differences persist after socioeconomic status and access to care are properly taken into account…

…Racially Admixed Populations

Although studies of population genetics have clustered persons into a small number of groups corresponding roughly to five major racial categories, such classification is not completely discontinuous, because there has been intermixing among groups both over the course of history and in recent times. In particular, genetic admixture, or the presence in a population of persons with multiple races or ethnic backgrounds, is well documented in the border regions of continents and may represent genetic gradations (clines) — for example, among East Africans (e.g., Ethiopians) and some central Asian groups. In the United States, mixture among different racial groups has occurred recently, although in the 2000 U.S. Census, the majority of respondents still identified themselves as members of a single racial group. Genetic studies of black Americans have documented a range of 7 to 20 percent white admixture, depending on the geographic location of the population studied. Despite the admixture, black Americans, as a group, are still genetically similar to Africans. Hispanics, the largest and fastest growing minority population in the United States, are an admixed group that includes white and Native American ancestry, as well as African ancestry. The proportions of admixture in this group also vary according to geographic region.

Although the categorization of admixed groups poses special challenges, groups containing persons with varying levels of admixture can also be particularly useful for genetic-epidemiologic studies. For example, Williams et al. studied the association between the degree of white admixture and the incidence of type 2 diabetes mellitus among Pima Indians. They found that the self-reported degree of white admixture (reported as a percentage) was strongly correlated with protection from diabetes in this population. Furthermore, as noted above, information on race or ethnic background can provide important clues to effects of culture, access to care, and bias on the part of caregivers, even in genetically admixed populations. It is also important to recognize that many groups (e.g., most Asian groups) are highly underrepresented both in the population of the United States and in typical surveys of population genetics, relative to their global numbers. Thus, primary categories that are relevant for the current U.S. population might not be optimal for a globally derived sample…

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