Population Genetic Structure and Origins of Native Hawaiians in the Multiethnic Cohort Study

<div><p>The population genetic structure of Native Hawaiians has yet to be comprehensively studied, and the ancestral origins of Polynesians remain in question. In this study, we utilized high-resolution genome-wide SNP data and mitochondrial genomes of 148 and 160 Native Hawaiians, respectively, to characterize their population structure of the nuclear and mitochondrial genomes, ancestral origins, and population expansion. Native Hawaiians, who self-reported full Native Hawaiian heritage, demonstrated 78% Native Hawaiian, 11.5% European, and 7.8% Asian ancestry with 99% belonging to the B4 mitochondrial haplogroup. The estimated proportions of Native Hawaiian ancestry for those who reported mixed ancestry (i.e. 75% and 50% Native Hawaiian heritage) were found to be consistent with their self-reported heritage. A significant proportion of Melanesian ancestry (mean = 32%) was estimated in 100% self-reported Native Hawaiians in an ADMIXTURE analysis of Asian, Melanesian, and Native Hawaiian populations of K = 2, where K denotes the number of ancestral populations. This notable proportion of Melanesian admixture supports the “Slow-Boat” model of migration of ancestral Polynesian populations from East Asia to the Pacific Islands. In addition, approximately 1,300 years ago a single, strong expansion of the Native Hawaiian population was estimated. By providing important insight into the underlying population structure of Native Hawaiians, this study lays the foundation for future genetic association studies of this U.S. minority population.</p> </div

Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population

<div><p>Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes <i>LDLRAD1</i>, <i>SLC19A1</i>, <i>FGFBP3</i>, <i>CASP5</i>, <i>MMAB</i>, <i>SLC16A6</i>, and <i>INS-IGF2</i>. In prostate cancer, one of the most associated SNPs was in the gene <i>GPRC6A</i> (rs2274911, <i>Pro91Ser</i>, OR = 0.88, P = 1.3×10⁻⁵) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as <i>F13A1</i>, <i>ANXA4</i>, <i>MANSC1</i>, and <i>GP6.</i> For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in <i>LDLRAD1</i>, p = 2.5×10⁻⁷ only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.</p> </div

ADMIXTURE clustering of Native Hawaiians for K = 5 (A) and K = 6 (B). <b>Figures 1A and 1B</b> illustrate the clustering of Native Hawaiians and HGDP samples based on GWAS data.

<p>Each vertical bar represents an individual's proportion of K ancestral clusters (i.e. color) as estimated by ADMIXTURE.</p

Multi-Dimensional Scaling analysis of GWAS data.

<p>HGDP representative samples with European, East Asian and Oceanian ancestry and are plotted against Native Hawaiians with various degrees of self-reported ancestry in MDS dimensions.</p

Principal components plots of AABC and selected HapMap samples.

<p>Principal components plots of AABC and selected HapMap samples.</p

Native Hawaiian specific mitochondrial SNP with minimum allele frequency >1%.

<p>Native Hawaiian specific mitochondrial SNP with minimum allele frequency >1%.</p

Plot of non-centrality parameter for the Bourgain test for a case-control study using two incompletely admixed populations as sources of cases and controls respectively.

<p>The parameters chosen refer to a test of a variant associated with disease which has 40 percent overall allele frequency and which is associated with a 10 percent difference in frequency between cases and controls (OR = 1.5 per copy). Cases are assumed to have average admixture percentage of 20 percent and controls 25 percent. The within population heterogeneity is specified by a single common heterogeneity parameter as used in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1001096#pgen-1001096-g001" target="_blank">Figure 1</a>.</p

Supervised ADMIXTURE results for K = 2 using Native Hawaiians, East Asian and Oceanian populations.

<p>Supervised ADMIXTURE results for K = 2 using Native Hawaiians, East Asian and Oceanian populations.</p

Average of each ancestral clustering estimated by ADMIXTURE for K = 5 and K = 6.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047881#pone-0047881-g002" target="_blank">Figures 2A and 2B</a> illustrate the mean values for each proportion of ancestry based on GWAS data. Pop1-6 are the ancestral populations representing the European, African, East Asian, American, Oceanian, and Hawaiian populations, respectively.</p

Plot of the density function of beta distributions parameterized by mean and heterogeneity factor .

<p>On each subplot the density is shown for two choices of namely  = 0.2 (solid line) and  = 0.25 (dotted lines).</p