Additional file 1: of Stepwise approach to SNP-set analysis illustrated with the Metabochip and colorectal cancer in Japanese Americans of the Multiethnic Cohort

Detailed characterization of genes and pathways used in the analysis. Supplementary Material. Detailed characterization of genes and SNPs used in the analysis. (DOCX 51 kb

Additional file 2: Table S1. of Sex and ethnic/racial-specific risk factors for gallbladder disease

Distribution of Risk Factors among MEC participants by sex and race/ethnicity. This table shows the distribution of risk factors in the MEC by sex and race/ethnicity. (DOCX 16 kb

Table3_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.xlsx

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

Table7_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.xlsx

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

Table2_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.xlsx

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

Table4_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.xlsx

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

Image2_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.pdf

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

Table5_Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.xlsx

Background<p>Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.</p>Methods and Results<p>We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10⁻⁶), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10⁻⁵) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10⁻⁵) and Latinos (OR = 1.03; p = 2.2 × 10⁻⁸), but not in Japanese (OR = 1.01; p = 0.11).</p>Conclusions<p>While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.</p

ANM Discovery–SNPs associated with age at natural menopause (ANM) in African American women from the PAGE Study.

<p>Tests of association at p≤1E-04 from single SNP linear regressions adjusted for study site and principal components in 1,860 African American women from the PAGE Study are shown. For each significant test of association, the chromosome, rs number, nearest gene, location, coded allele, beta, standard error (SE), and p-value are given. Genes listed are nearest genes to the SNP as measured from the transcription start site for upstream SNPs or the transcription stop site for downstream SNPs. Abbreviations: CAF, coded allele frequency.</p

Regional Association Plots for Age at Natural Menopause in African American women in the PAGE Study.

<p>Locus Zoom plots for selected gene regions in age at natural menopause analysis. Vertical axis is the –log₁₀ of the p-value, the horizontal axis is the chromosomal position. Each dot represents a SNP tested for association with age at natural menopause in 1,860 African American women from the PAGE Study. Linkage disequilibrium between the most significant SNP, listed at the top of each plot, and the other SNPs in the plot is shown by the r² legend in each plot. (A) Locus Zoom plot for the <i>APOE</i> region, with rs78916952 the most significant SNP in the region. (B) Locus Zoom plot for the <i>MCM8</i> region; rs237688 is the most significant SNP in the plot region. (C) <i>FSHB</i> region Locus Zoom plot; rs605765 is the most significant SNP in the plot region. (D) Locus Zoom plot of the <i>BRSK1</i> region with rs11672111 as the most significant SNP in the plot region.</p