Supplementary Table 1. Bipolar, schizophrenia, and controls were analyzed for 362 mtdna SNPs using
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1 Supplementary Tables Supplementary Table 1. Bipolar, schizophrenia, and controls were analyzed for 362 mtdna SNPs using Affymetrix 6 cel files. The number of cases and controls of European ancestry from the USA (GAIN and GRU) and the UK (WTCCC2) are shown, note that overlap in controls in GAIN cohorts were removed prior to analysis. Group GAIN (N) GRU (N) WTCCC2 (N) Total used in study Controls Bipolar Disorder Schizophrenia Total 6040
2 Supplementary Table 2. Correlation coefficients between age and common deletion levels sorted by most significant brain regions, statistically significant correlations are shown in bold. A multivariate R 2 test showed a significant effect of age across the 11 brain regions (p = 0,.024). Region Multiple R Multiple R² Adjusted R² F p CAUN NACC AMY CB HIPP ACC OFC DLPFC SN THAL PUT
3 Supplementary Table 3. The correlation matrix for the common deletion for all subjects is shown with all bolded Pearson correlations in red (p < 0.05). The correlation with age is shown for each region and showed significant positive correlation with the percentage of common mtdna deletion for 7 of 11 brain regions. AMY ACC CAUN CB DLPFC HIPP NACC OFC PUT SN THAL AGE AMY ACC CAUN CB DLPFC HIPP NACC OFC PUT SN THAL AGE All p-values are < 0.05 when r 0.602, p < if r 0.775, p < if r 0.869, p < if r 0.923, p < if r 0.954, p < if r 0.972, p < if r
4 Supplementary Table 4. Post hoc comparisons of the mean percentage of common deletion in brain region. The corrected p-values for multiple comparisons using Tukey's Honest Significant Difference test are shown for each regional-comparison. Two highest regions of common deletion are the CN (caudate nucleus) and SN (substantia nigra), while the cerebellum showed 39 fold less compared to CN and SN. These three regional differences account for most of the significant post-hoc differences observed, while the remaining regions AMY, ACC, DLPFC, HIPP, NACC, OFC, PUT, THAL were not significantly different when corrected for multiple comparisons. The nominal least significant differences test (p < 0.05) was found on 29 of regional 55 comparisons (not shown) and lowest nominal p-value of 1.8 x was observed for the CB compared to the SN. Mean Percentage Common Deletion ± Standard Error 2.12 ± 2.02 ± 4.70 ± 0.12 ± 1.81 ± 1.90 ± 2.62 ± 2.08 ± 2.73 ± 4.93± 0.49 ± Tukey's HSD p-values corrected for multiple post hoc comparisons Region AMY ACC CAUN CB DLPFC HIPP NACC OFC PUT SN THAL AMY ACC CAUN CB DLPFC HIPP NACC OFC PUT SN THAL
5 Supplementary Table 5. Complete list of the observed novel* or rare homoplasmic mutations in brain compared to the rcrs. Gene function column refers to NC = non coding, PP = polypeptide, PS= protein synthesis. Position Reference Sequence Mutation Gene Gene Function Number of Subjects 26 C T D-Loop NC 1 39 C T D-Loop NC A G D-Loop NC C T D-Loop NC C A D-Loop NC A C D-Loop NC T C D-Loop NC 2 PhyloTree Build 11 Genbank 5102 sequences mtdna (%) 224 T C D-Loop NC 1* % 225 G A D-Loop NC T C D-Loop NC G A D-Loop NC T C D-Loop NC C T D-Loop NC T insertion D-Loop NC A G D-Loop NC A C D-Loop NC T C 12srRNA PS C T 16srRNA PS G A 16srRNA PS A G 16srRNA PS T C 16srRNA PS T C 16srRNA PS A G 16srRNA PS G A ND1 PP 1 hg P3b1 (e.g. EF061153); also FJ within hg U5a1d2 hg L1c3b2 (sequence 597 in Howell et al. 2004) 0.23% 0.02%
6 3336 T C ND1 PP T C ND1 PP A G ND1 PP G A ND1 PP G A ND1 PP T C ND2 PP G A ND2 PP T C ND2 PP C T ND2 PP 1 Howell 44=072U 0.02% 4924 G C ND2 PP 1 DQ % 5082 T C ND2 PP G A ND2 PP A G ND2 PP C A ND2 PP A G ND2 PP A G ND2 PP A G trna Trp PS 1 hg M6a (e.g. FJ383308) 0.078% 5686 A T trna Asn PS 1* % 5786 T C OL NC A T COI PP C T COI PP T C COI PP T A COI PP T C COI PP A G COI PP C T COI PP G A COI PP 1 hg L0f1 (e.g. EU092870); hg L1c1a1a1 (e.g. EU273490); hg L1c1c (EU092717); hg U4d1a (e.g. GU123021) 0.58% 6578 A G COI PP 1* % 6734 G A COI PP G A COI PP C T COI PP 1
7 7151 C T COI PP C T COII PP 1* % 7844 A G COII PP A T COII PP T C NC7 NC C T ATPase 8 PP A G ATPase 8 PP G A ATPase 8 PP A C ATPase 6 PP T C ATPase 6 PP A G ATPase 6 PP 1 hg T2c1a (e.g. EF556160) hg U4b1a1a (e.g. AY882388) 0.07% 0.03% 8945 T C ATPase 6 PP 1 AP % 9126 T A ATPase 6 PP 1* % 9467 T C COIII PP T C COIII PP T C ND4L PP 1 hg R0a1a2 (e.g. HM185258) 0.02% T C ND4 PP 1* % A G ND4 PP A G ND4 PP 1* % T C ND4 PP T C ND4 PP C T ND4 PP A C ND4 PP A G ND4 PP G A ND4 PP C T ND5 PP T C ND5 PP A G ND5 PP T C ND5 PP C T ND5 PP A G ND5 PP A C ND6 PP T A ND6 PP 1 hg A2i (e.g. EU431080) 0.15%
8 14596 A G ND6 PP C T Cytb PP G A Cytb PP A G Cytb PP 1 EU ,EU % C T Cytb PP 1 EF % T C Cytb PP T C Cytb PP A G Cytb PP T C Cytb PP G A Cytb PP T C Cytb PP T C trna Thr PS A G trna Thr PS C T trna Pro PS C T D-Loop NC T C D-Loop NC C T D-Loop NC C T D-Loop NC G C D-Loop NC C T D-Loop NC C A D-Loop NC A G D-Loop NC A G D-Loop NC C T D-Loop NC C T D-Loop NC C T D-Loop NC C T D-Loop NC G A D-Loop NC A G D-Loop NC A G D-Loop NC C T D-Loop NC C T D-Loop NC T C D-Loop NC C T D-Loop NC G A D-Loop NC 2
9 NC = non coding PP = polypeptide PS= protein synthesis
10 revised Cambridge Reference Sequence Supplementary Table 6. Novel or rare homoplasmic variants were counted for numbers of transitions and transversions in complete mtdna genome of 23 individuals from DLPFC. There were 131 unique transitions and 17 unique transversions in the dataset. Shaded numbers are transitions, unshaded numbers are transversions. Transition / Transversion Observed Sequence A G C T A G C T
11 Supplementary Table 7. Summary of function for novel and rare homoplasmic variants detected in 23 mtdna sequences from the DLPFC. Summary of function Protein Synthesis (PS) Polypeptide (PP) Noncoding region (NC) Rare homoplasmic variants Novel homoplasmic variants
12 Supplementary Table 8. Summary of total number of transitions and transversions per genome for 23 DLPFC samples for each diagnosis. Coding Per Genome Transition Transversion Total Transition/Transversion BP (N=4) C (N=10) MDD (N=5) SZ (N=4) Noncoding Per Genome Transition Transversion Total Trans/Transv BP (N=4) C (N=10) MDD (N=5) SZ (N=4)
13 Supplementary Table 9. Distribution of diagnosis by haplogroup for 23 DLPFC samples. These postmortem samples were sequenced by Illumina GAII, and consensus sequences arranged in a phylogenetic tree (Figure 4). The number of samples is too low for statistical testing of haplogroup prevalence of psychiatric disorder. Haplogroup # of subjects Diagnosis L1c3b2 1 C D1f 1 MD N1a1a2 1 MD I2 1 MD I1 1 C T1a1 1 SZ H1 2 C, MD H1g 1 SZ H1e 1 C H10 1 BD H2a2a 1 C H26 1 C H5 1 C HV1a2 1 C U2e1 1 SZ U2e2a 1 C U5a1 1 SZ U5a1d2 1 BD X2 1 BD X2c1 3 C, BD, MD
14 Supplementary Table 10. Case and control counts of nominally significant SNPs from association with pooled groups (BD + SZ), BD, and SZ are shown. Extra mtsnps are shown in this table, however, were not listed in the main paper, as the no call (NC) rate/ MAF was above 20% suggesting errors that could inflate p-value. SNP Group NC rate NC rate/ MAF NC AA BB SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C
15 SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ SNP_A BD SNP_A C SNP_A SZ
16 Supplementary Figures Supplementary Figure 1. The correlation between age (x-axis) and mtdna common deletion (y-axis) showing the anterior cingulate cortex, cerebellum, amygdala, caudate nucleus, DLPFC, hippocampus, nucleus accumbens, orbital frontal, putamen, substantia nigra, and thalamus.
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22 Supplementary Figure 2. Post hoc comparisons of each brain region and mtdna common deletion corrected p-values for multiple comparisons using Tukey's Honest Significant Difference test (HSD p-values shown Supplementary Table 4). The two regions with the most mtdna common deletion are the CN (caudate nucleus) and SN (substantia nigra).
23 Supplementary Figure 3. There was a significant effect of age on percentage of the mtdna common deletion in DLPFC samples from Cohort 2. The correlation between age and percent deletion was 0.41 (p = 0.02).
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