Genetic Background of Patients from a University Medical Center in Manhattan: Implications for Personalized Medicine

Background: The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings: To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within-and between-group heterogeneity. Conclusion: As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.National Heart Lung and Blood Institute (NHLBI/NIH)[RO1 HL53353]Andrea and Charles Bronfman Philantropie

Multidimensional scaling plots for all samples (TOP) and only biobank samples (BOTTOM).

<p>Plots of subjects in the 1^st and 2^nd dimensions (left column), 2^nd and 3^rd dimensions (middle column), and 3^rd and 4^th dimensions right column). Abbreviation for samples: African American biobank sample (ANY); European American biobank sample (ENY); Hispanic American biobank sample (HNY); African ancestry in Southwest USA (ASW); Mexican ancestry in Los Angeles, California (MEX); Yoruba from Nigeria (YOR); African American from Maywood, Illinois (AMW); Brazilians from Brazil (BRZ).</p

Canonical correlation based on window-wide local PCs for biobank samples and selected external samples.

<p>Each circle represents the squared coefficient of the largest canonical correlation between the first 10 local PCs of a local 20 Mb-window and the first 10 global PCs. Abbreviation for samples: African American biobank sample (ANY); European American biobank sample (ENY); Hispanic American biobank sample (HNY); African American from Maywood, Illinois (AMW); CEPH (Utah residents with ancestry from northern and western Europe (CEU); Brazilians from Brazil (BRZ).</p

Figure 5

<p><b>a:</b> Linkage disequilibrium structure (Top) and organization of haplotypes harboring published obesity variants (rsIDs indicated with blue boxes) in <b>FTO</b> gene in biobank sample of African Americans (left column), European Americans (middle column), and Hispanic Americans (right column). <b>b:</b> Linkage disequilibrium structure (Top) and organization of haplotypes harboring published obesity variants (rsIDs indicated with blue boxes) in <b>MC4R</b> gene in biobank sample of African Americans (left column), European Americans (middle column), and Hispanic Americans (right column).</p

Characteristics of subjects.

<p><i>Mean ± SD</i>.</p

Population structure results for ancestral populations <i>K</i> = 2 to <i>K</i> = 6.

<p>Each subject is represented by a thin vertical line colored in proportion to their estimated ancestry within each cluster. The colors represent the proportion of inferred ancestry from each of the ancestral populations within each specific K value. Abbreviation for samples: African American biobank sample (ANY); European American biobank sample (ENY); Hispanic American biobank sample (HNY); African ancestry in Southwest USA (ASW); Mexican ancestry in Los Angeles, California (MEX) ; Yoruba from Nigeria (YOR); African American from Maywood, Illinois (AMW); Brazilians from Brazil (BRZ).</p

Population structure results for <i>K</i> = 2 ancestral populations sorted by ancestry proportions for African American biobank sample (ANY) and Hispanic American biobank sample (HNY) (Top) and pooled sample of both ANY and HNY (Bottom).

<p>Population structure results for <i>K</i> = 2 ancestral populations sorted by ancestry proportions for African American biobank sample (ANY) and Hispanic American biobank sample (HNY) (Top) and pooled sample of both ANY and HNY (Bottom).</p