Results of association tests with birth rate in Hutterite men.

1<p>All three genotypes were tested individually.</p>2<p>People carrying Met/Val and Val/Val genotypes were combined and tested against Met/Met homozygotes.</p

Birth rates in Amish men by Met470Val genotypes (<i>P</i> = 0.22).

<p>Birth rates in Amish men by Met470Val genotypes (<i>P</i> = 0.22).</p

Frequencies of the <i>CFTR</i> haplotypes in the Hutterites.

<p>Frequencies of the <i>CFTR</i> haplotypes in the Hutterites.</p

Met470Val genotypes and fertility in Hutterite men.

<p>(A) Cumulative plot of the number of years from marriage (y-axis) to each birth (x-axis) by genotype. Black horizontal lines show the means and whiskers show standard errors. (B) Box plot and distribution of the number of births (y-axis) among men by genotype (x-axis) for men who are married at least 11.5 years (mean number of years from marriage to last birth for the men in this sample). (C) Survival curves showing the proportion of men reaching the 6^th birth (equal to the mean and median of number of births among men in this sample) (y-axis) by 6 to 20 years of marriage (x-axis) by genotype. The distributions of total length of marriages are similar for men in both genotype groups (not shown).</p

Geographic distribution of the Met470Val polymorphism in HGDP samples.

<p>The relative frequencies of each allele are shown as blue (ancestral Met470 allele) and orange (derived Val470 allele) pie slices.</p

Population genetic parameters of the <i>CFTR</i> Met470Val locus.

<p>(A) Haplotype blocks +/− 500 kb around Met470Val locus in HapMap CEU (phase II) samples. The arrow indicates the location of Met470Val; the blue vertical line shows the ancestral Met470 allele and the red vertical line shows the derived Val470 allele. A continuous block of the same color represents the haplotypes shared between individuals. Haplotypes on the Met470 background are shorter and more variable compared to those on Val470 background. (B) Decay of extended haplotype homozygosity (EHH) around the Met470Val locus in the same data as in (A). The blue plot represents the decay of haplotypes on the ancestral (Met) allele background; the red plot represents the decay of haplotypes on the derived (Val) allele background. The Y-axis shows the EHH, defined as the probability that two randomly chosen chromosomes are homozygous at all SNPs for the entire interval from the core SNP at distance <i>x </i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000974#pgen.1000974-Sabeti2" target="_blank">[37]</a>. EHH probability drops below 0.5 at approximately 300 kb around Met470Val on haplotypes carrying the Val470 allele, compared to <20 kb on haplotypes carrying the Met allele. The iHS corresponds to the natural logarithm of the ratio of areas under the ancestral and derived allele EHH curves, standardized to be independent of the allele frequencies. A negative iHS implies that the haplotypes on derived allele background are longer than those on ancestral background <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000974#pgen.1000974-Voight1" target="_blank">[23]</a>. (C–E) Genome-wide distributions of (C) Fst values, (D) iHS scores and (E) Fst and iHS scores for SNPs in HapMap phase II data. Black lines (and filled circle in E) show the location of the Met470Val SNP in each distribution. Proportions of SNPs with more extreme values are shown on the plots as empirical <i>P</i>-values.</p

Frequencies of the <i>CFTR</i> polymorphisms.

1<p>Allele frequencies in the Hutterite men.</p>2<p>Allele frequencies in the Amish men.</p

<i>CFTR</i> Met470Val genotypes and birth rate in Hutterites men.

<p>The residuals of birth rate, corrected for relatedness is shown on the y-axis, and the number of Val470 alleles at the <i>CFTR</i> Met470Val locus is shown on the x-axis. Sample sizes for each genotype group are shown under x-axis. Each grey circle corresponds to an individual subject. Red horizontal lines show the means and black whiskers show the standard errors. (A) Met470Val genotype (Model 1); grouped by 0 (Met/Met), 1 (Met/Val) or 2 (Val/Val) copies of the Val allele; (B) Met470Val genotype (Model 2) with Val/Val and Met/Val men combined.</p

Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies <i>HLA-F</i> and <i>TAP2</i> as Fecundability-Associated Genes

<div><p>Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD (<i>r</i>² >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the <i>TAP2</i> gene (<i>P</i> = 1.3x10^-4) and the <i>HLA-F</i> gene (<i>P</i> = 4.0x10^-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.</p></div

Combined analysis of rs2071473 and rs2523393 in the Hutterites.

<p>Time-to-pregnancy curves stratified by homozygosity for risk alleles at both eSNPs. The numbers in parentheses are the number of intervals included for women in each group. The number of women in each group is 64 (neither CC nor GG), 37 (CC or GG) and 15 (CC and GG).</p