第809回千葉医学会例会・第一外科教室談話会 64.

<p>RR, relative risk.</p

Supplementary_figure_and_Tables - Transcriptome-Wide Association Study Identifies Susceptibility Loci and Genes for Age at Natural Menopause

<p>Supplementary_figure_and_Tables for Transcriptome-Wide Association Study Identifies Susceptibility Loci and Genes for Age at Natural Menopause by Jiajun Shi, Lang Wu, Bingshan Li, Yingchang Lu, Xingyi Guo, Qiuyin Cai, Jirong Long, Wanqing Wen, Wei Zheng, and Xiao-Ou Shu in Reproductive Sciences</p

Estimated haplotype phylogeny at the <i>FTO</i> locus.

<p>Haplotypes with frequencies ≥0.05 are demonstrated in the figure, apart from H1-1, H1-2, H1-3, H3-1 and H3-3, which could be generated by recombination. Also see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone-0101329-t002" target="_blank">Table 2</a> and Table S5.</p

Systematic Fine-Mapping of Association with BMI and Type 2 Diabetes at the <i>FTO</i> Locus by Integrating Results from Multiple Ethnic Groups

<div><p>Background/Objective</p><p>The 16q12.2 locus in the first intron of <i>FTO</i> has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at <i>FTO</i>, we performed a systematic approach consisting of two parts.</p><p>Methods</p><p>The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.</p><p>Results</p><p>We first examined the LD relationship between <i>FTO</i> SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target <i>FTO</i> region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations—Japanese, Vietnamese, Sri Lankan and Chinese (<i>n</i>≤26,109 for BMI association and <i>n</i>≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for <i>FTO</i>.</p><p>Conclusions</p><p>Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations—Europeans, Asians and Africans—are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.</p></div

SNP–BMI association at the <i>FTO</i> locus in multiple ethnic groups.

<p>In each group, two separate panels were characterized and combined by meta-analysis: Amagasaki and Fukuoka panels in Japanese, Hanoi and Thai Binh panels in Vietnamese, and Ragama and estate panels in Sri Lankans (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#s2" target="_blank">Methods</a>).</p><p>BETA and SEM of each trait are shown as z-score after adjustment for standard deviation.</p><p>Besides the SNPs listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone-0101329-t002" target="_blank">Table 2</a>, two SNPs—rs62033408 and rs72805612 (in complete LD with rs7188250)—were tested for BMI association, because these showed significant association in African-Americans <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone.0101329-Peters1" target="_blank">[7]</a>.</p><p><i>P</i>_hetero; P-value for Inter-population heterogeneity among three Asian groups.</p><p>rs9939609 is in complete LD (<i>r²</i> = 1.000) with rs62033400 in both HapMap CEU and HapMap JPT+CHB, whereas they are not in strong LD (<i>r²</i> = 0.065) in HapMap YRI. In African Americans, rs62033400 showed strong association with BMI (<i>P</i> = 1.1E-5). In HapMap JPT+CHB, rs9923544 and rs9941349 are in complete LD (<i>r²</i> = 1.00).</p><p>Results for Europeans are drawn from the GIANT consortium (<a href="http://www.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium" target="_blank">http://www.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium</a>) and those for African Americans are from the published data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone.0101329-Peters1" target="_blank">[7]</a>; the effect allele frequencies in Europeans are from HapMap CEU data.</p><p>*In European populations, the results for a proxy, rs1558902, which is in complete LD (<i>r²</i> = 1.0) with rs1421085 in HapMap CEU, were reported.</p

Plots of SNP–trait association and SNP partitioning for the 16q12.2/<i>FTO</i> region in Japanese (type 2 diabetes, a) and Europeans (type 2 diabetes, b; BMI, c).

<p>Association results for Europeans are drawn from the published studies <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone.0101329-Zeggini1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone.0101329-Speliotes1" target="_blank">[20]</a>. a, b and c each contain three panels. In the top panels, all assayed/imputed SNPs in the GWA scan (that passed the quality control) are plotted with their −log10 (<i>p-</i>values) for type 2 diabetes (a and b) and BMI (c) against chromosome position (in Mb): genotypes are imputed to the HapMap Phase 2 data set. In the second panels, the genomic locations of RefSeq genes with intron and exon structure (NCBI Build 37) are displayed. The third panels show the plots for the intron-1 <i>FTO</i> region, where the associated SNPs are partitioned into seven clusters and colored accordingly (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#s2" target="_blank">Methods</a>).</p

<i>FTO</i> Haplotypes involving index SNPs and their association with BMI and type 2 diabetes.

<p>It is assumed that a cluster of base-substitutions (involving rs1421085, rs3751812, rs9941349, rs56137030, rs17817964, and rs12149832) initially occurred, followed by another cluster of base-substitutions (involving rs9939609) within the target interval at <i>FTO</i>. Then, presumably the underlined alleles were produced by either recombination or recurrent base-substitutions that occurred independently at each SNP (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone-0101329-g002" target="_blank">Figure 2</a> and Table S5). Ancestral types of alleles are shown in bold letters.</p><p>In the estimates of haplotype frequency, they are labelled with “Low”when the frequency is <0.004 (except for H1–2 in the European-ancestry population).</p><p>There is recombination between rs7206790 and other assayed SNPs. For rs7206790, haplotypes with recombination are further split by two alleles; the major and minor alleles are shown in the left and right sides of the slash for the corresponding haplotypes.</p><p>rs3751812 was genotyped in T2D-association samples alone (but not in BMI-association samples) because rs3751812 and rs9939609 could not be differentiated due to the absence of H2 haplotype class in populations of East Asian and European ancestry. BMI/T2D association in each population was calculated by using haplotype-based linear/logistic regression with PLINK. The effect sizes of three Asian populations (Japanese, Vietnamese and Sri Lankan) were combined by a fixed-effect meta-analysis, while SriLankan data were not used for H1-3 and H3-4 because of the low frequency.</p><p>*Besides the SNPs tagging individual LD clusters that were drawn from T2D association results (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone-0101329-g001" target="_blank">Figure 1</a>), rs1421085 and rs56137030 were characterized in the present study, because they were reported to be promising candidates for causal variants at <i>FTO</i> in African American populations <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101329#pone.0101329-Peters1" target="_blank">[7]</a>.</p><p>**Test of heterogeneity in effect size between the three populations meta-analyzed in the present study.</p

Overlap of SNPs associated with BMI at <i>FTO</i>.

<p>The Venn diagram illustrates the number of SNPs that show association with BMI in any of three ethnic groups. The total number of associated SNPs in individual ethnic groups is listed in parentheses after the ethnic group name.</p

Forest plot for prospective studies of adult height and prostate cancer.

<p>Overall prostate cancer (A); aggressive prostate cancer (B). RR, relative risk.</p

PRISMA flow chart for studies included in the meta-analysis.

<p>PRISMA flow chart for studies included in the meta-analysis.</p