Meta-analysis of previously reported PCa and CRC associations including replication results from the present study.

a<p>^/SNP identifier based on NCBI SNP database;</p>b<p>^/meta-analysis was done for minor allele (MA).</p

The GWAS-selected SNPs association with AD, CRC or PCa, considering allelic and additive models.

<p>Bold denotes significant association (<i>p</i><0.05). G1 vs. G2; compared groups of cases and controls, respectively, MA; minor allele (+) strand, F1, F2; frequency of MA in the case and control groups, respectively, OR; odds ratio, CI; confidence interval, N; control, PCa; prostate cancer, AD; adenoma, CRC; colorectal cancer, F; female, M; male.</p>a<p>^/SNP identifier based on NCBI SNP database;</p>b<p>^/NCBI ID of genes localized in proximity to the SNPs of interest (source: HapMap).</p

Group statistics of the GWAS and the replication study cohorts.

<p>The GWAS validation panel indicates numbers of patients (N) enrolled in the GWAS, after excluding microarrays that did not meet quality control criteria based on the PCA results. The ‘Range’ and ‘Median’ values regard age of cases and controls in respective groups. Both GWAS validation and replication analyses were done using respective individual patient TaqMan® genotyping. The TaqMan® genotyping data was subjected to a quality filtration using the 5% threshold of per-individual maximum genotype missingness (see ‘<i>Statistical analyses – individual genotyping</i>’).</p

Pooled-DNA allelotyping GWAS and technical validation of GWAS selections using individual patient TaqMan genotyping.

<p>Technical validation was performed by individual typing of DNA samples from the same study cohorts used for pooled-DNA GWAS. The allele frequency distribution and χ²-test <i>p</i>-values were taken into account. G1 vs. G2; compared groups of cases and controls, respectively, MA; minor allele (+) strand, F1, F2; frequency of MA in the case and control groups, respectively, OR; odds ratio, CI; confidence interval, N; control, PCa; prostate cancer, AD; adenoma, CRC; colorectal cancer, F; female, M; male.</p>a<p>^/SNP identifier based on NCBI SNP database;</p>b<p>^/SNP identified in two independent comparisons.</p

The literature-selected SNPs significant associations with AD, CRC or PCa, considering allelic and additive models.

<p>Bold denotes significant association (<i>p</i>-value_cor<0.05). MA; minor allele (+) strand, G1 vs. G2; compared groups of cases and controls, respectively, OR; odds ratio, CI; confidence interval, N; control, PCa; prostate cancer, AD; adenoma, CRC; colorectal cancer, F; female, M; male.</p>a<p>^/SNP identifier based on NCBI SNP database;</p>b<p>^/NCBI ID of genes localized in proximity to the SNPs of interest (source: HapMap).</p

Functionally relevant regions of the D-loop.

a<p>functionally relevant regions of the D-loop adapted from <a href="http://www.mitomap.org" target="_blank">www.mitomap.org</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-RuizPesini1" target="_blank">[32]</a>, ^bmtDNA position according to rCRS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Andrews1" target="_blank">[29]</a>, <b>^c</b>LSP region alone also indicated at m.392 to m.445 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Chang1" target="_blank">[49]</a>, ^dHSP2 was indicated at <a href="http://www.mitomap.org" target="_blank">www.mitomap.org</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-RuizPesini1" target="_blank">[32]</a> as m.645 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Montoya1" target="_blank">[52]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Yoza1" target="_blank">[54]</a>, however, more recent investigation mapped start of HSP2 at m.644 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Zollo1" target="_blank">[26]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Lodeiro1" target="_blank">[27]</a>; m.632 to m.655 was selected as HSP2 region, as Lodeiro et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Lodeiro1" target="_blank">[27]</a> randomized these 24 nucleotides around the transcription start and did not detect transcription <i>in vitro</i>, thus, these 24 nucleotides might be important HSP2 control elements (e.g. transcription factor binding sites).</p><p>CE, control element; CSB, conserved sequence block; ETAS, extended termination associated sequence, HSP, heavy strand promoter; HV, hypervariable region; LSP, light strand promoter; mtTF1 BS, mitochondrial transcription factor A (TFAM) binding side (TFAM, formerly known as mtTF1), OXPHOS, oxidative phosphorylation; TAS, termination associated sequence.</p

Nominally associated mtDNA SNPs in discovery and follow-up in confirmation.

a<p>mtDNA position according to rCRS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Andrews1" target="_blank">[29]</a>.</p>b<p>MAF, minor allele frequency.</p>c<p>95% confidence of odds ratio for minor allele.</p>d<p>Fisher's exact test, two-sided, p-values below 0.05 are highlighted in bold.</p

Detected length heteroplasmies.

<p>Detection of length heteroplasmies, i.e. mixtures of various lengths of a certain mtDNA region in one individual, occurred at four locations in the D-loop (m.16024 to m.576), predominantly at poly-C tracts. Numbering according to rCRS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094882#pone.0094882-Andrews1" target="_blank">[29]</a>.</p

Nominally associated mt haplogroups in discovery and follow-up in confirmation.

a<p>only individuals with HaploGrep's quality ≥90% were included (∼96% of all individuals).</p>b<p>95% confidence interval for odds ratio.</p>c<p>Fisher's exact test, two-sided, p-values below 0.05 are highlighted in bold.</p

a–d): eQTLs with simultaneous impact on expression levels of at least five genes in <i>trans</i>.

<p>a) Chromosome 12. The eQTL was located upstream of <i>lysozyme</i> (<i>LYZ</i>), a gene residing on chromosome <i>12q15</i>. It is associated with expression levels of the seven transcripts <i>cAMP responsive element binding protein 1 (CREB1), SHC SH2-domain binding protein 1 (SHCBP1), arylformamidase (AFMID), KIAA0101, ITPK1 antisense RNA 1 (ITPK1-AS1), EP300 interacting inhibitor of differentiation 2B (EID2B)</i>, and <i>CDKN2A interacting protein N-terminal like (CDKN2AIPNL)</i>. b) Chromosome 11. The eQTL was found intronic of the <i>hemoglobin beta</i> (<i>HBB</i>) gene on chromosome <i>11p15.4</i> and was associated with the regulation of 13 genes distributed across the genome in <i>trans</i>: <i>PWP1 homolog (PWP1), phosphatidylserine synthase 1 (PTDSS1), CCHC-type zinc finger, nucleic acid binding protein (CNBP), trafficking protein particle complex 11 (TRAPPC11), histone deacetylase 1 (HDAC1), WD repeat domain 59 (WDR59), G protein pathway suppressor 1 (GPS1), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1), aarF domain containing kinase 2 (ADCK2), deoxythymidylate kinase (thymidylate kinase) (DTYMK), WD repeat domain 37 (WDR37), spectrin repeat containing, nuclear envelope 2 (SYNE2)</i>, and <i>RAD51 paralog C (RAD51C)</i>. c) Chromosome 3. The eQTL on chromosome 3 was located intronic of the <i>rho guanin nucleotid exchange factor 3 (ARHGEF3)</i> gene at <i>3p14.3</i>. We observed a significant impact on the regulation of twelve genes, <i>integrin beta 5 (ITGB5), platelet glycoprotein IX (GP9), carboxy-terminal domain, RNA polymerase II, polypeptide A small phosphatase-like (CTDSPL), protein S alpha (PROS1), guanylate cyclase soluble subunit alpha-3 (GUCY1A3)</i>, <i>caldesmon 1 (CALD1)</i>, <i>tetraspanin 9 (TSPAN9), arachidonate 12-lipoxygenase (ALOX12), parvin beta (PARVB), N-acetyltransferase 8B (NAT8B), multimerin 1 (MMRN1)</i>, and <i>C-type lectin domain family 1, member B (CLEC1B)</i>. d) Chromosome 2. The eQTL upstream of <i>atonal homolog 8 (ATOH8)</i> residing on chromosome 2p11.2 exerts simultaneous impact on expression levels of six genes: <i>paroxysmal nonkinesigenic dyskinesia (PNKD)</i> and <i>calcium homeostasis modulator 1 (CALHM1)</i>, <i>zink finger protein 93 (ZNF93), dynein, light chain, roadblock-type 2 (DYNLRB2), growth hormone-releasing hormone receptor (GHRHR)</i>, and <i>MutL-homolog 3(MLH3)</i>.</p