The Impact of Mitochondrial and Nuclear DNA Variants on Late-Onset Alzheimer s Disease Risk
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- Ιάνθη Γεννάδιος
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1 Journal of Alzheimer s Disease 27 (2011) 1 12 IOS Press 1 Supplementary Data The Impact of Mitochondrial and Nuclear DNA Variants on Late-Onset Alzheimer s Disease Risk Aleksandra Maruszak a,, Krzysztof Safranow b, Wojciech Branicki c, Katarzyna Gawȩda-Walerych a, Ewelina Pośpiech c, Tomasz Gabryelewicz a, Jeffrey A. Canter d, Maria Barcikowska a and Cezary Żekanowski a a Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warszawa, Poland b Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Szczecin, Poland c Section of Forensic Genetics, Institute of Forensic Research, Kraków, Poland d Center for Human Genetic Research, Vanderbilt University Medical Center, Nashville, TN, US Handling Associate Editor: Russell Swerdlow Accepted 6 June 2011 Correspondence to: Aleksandra Maruszak, Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, Warsaw, Poland. Tel.: ; Fax: ; aleksandra.maruszak@gmail.com. ISSN /11/$ IOS Press and the authors. All rights reserved
2 2 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Figure 1. Summary of the main effects (A, B) and interaction model of two-factor (APOE4 status, rs1937) combinations (C) associated with high risk (dark box) or low risk (light box) for LOAD from MDR analysis (described in detail in Table 11). For each genotype combination, the number of cases (left bar in boxes) and control individuals (right bar in boxes) is displayed. APOE4+ status is indicated as 1, APOE4 as 0; TFAM rs1937 GG genotype is indicated as 2, GC as 1 and CC as 0. A) Results of MDR analysis for single locus model - APOE4 status. Testing Balanced Accuracy = 0,685, CVC 10/10, p = 0,0014; B) Results of MDR analysis for single locus model rs1937 (Search type: forced), Testing Balanced Accuracy = 0.513, p = 0.772; D) Results of MDR analysis for two-locus model APOE4 status rs1937 (Search type: forced; Testing Balanced Accuracy = 0.689, p = ). Supplementary Table 1 MtDNA polymorphisms, haplogroups and haplogroup clusters found associated with AD risk Polymorphism/Haplogroup/ Effect on Population LOAD/Control References haplogroup cluster LOAD risk group (N/N) m.4336t>c European Caucasians (USA) 62/125 [27] German 28/100 [28] mixed (USA)* 72/296 [29] mixed (USA)* 155/105 [30] m.11467a>g ADNI** 170/188 [25] m.10398a>g for males European Caucasians (USA) 989/328 [31] m.12308a>g for females European Caucasians (USA) 989/328 [31] ADNI 170/188 [25] m.12372g>a, m.9698c>t ADNI 170/188 [25] m.16270c>t HV Polish 222/252 [32] H Iranian 30/100 [33] symbolizes an increase and a decrease in AD risk; * Mixed population means that it comprised Africans, Asians and Europeans; **ADNI - Alzheimer s Disease Neuroimaging Initiative.
3 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD 3 Supplementary Table 1 Polymorphism/Haplogroup/ Effect on Population LOAD/Control References haplogroup cluster LOAD risk group (N/N) H5 citizens of Southern and Central Italy 936/776 [26] J French Canadians 69/83 [34] K neutralizes APOE4 effect Italian 213/179 [35] T French Canadians 69/83 [34] U neutralizes APOE4 effect Italian 213/179 [35] for males, for females European Caucasians(USA) 989/328 [31] Iranian 30/100 [33] ADNI 170/188 [25] symbolizes an increase and a decrease in AD risk; * Mixed population means that it comprised Africans, Asians and Europeans; **ADNI - Alzheimer s Disease Neuroimaging Initiative. Supplementary Table 2 Haplogroup H subhaplogroups with defining mtdna coding region polymorphisms. The primers used to amplify the fragment of mtdna sequence with particular polymorphism are also presented Subhaplogroup of mtdna Primers (5 3 ) Tm haplogroup H polymorphism H1 3010G>A F ACTCAATTGATCCAATAACTTGACC 60 C R GTAGATAGAAACCGACCTGGATTAC H G>A F GGCTCACATCACCCCATAAA 56 C R GCTTGATGCTTGTTCCTTTTG H2 1438A>G F TGGCAAGAAATGGGCTACAT 60 C R GTGTGTACGCGCTTCAGG H3 6776T>C F GTCACCCTGAAGTTTATATTCTTATCCTAC 60 C R GTGTGTCTACGTCTATTCCTACTGTAAACA H4a 4024T>A F CCCTTCGCCCTATTCTTCAT 59 C R GGGAGGTTAGAAGTAGGGTCTTG H4 5004T>C F CCATCATAGCAGGCAGTTGA 58 C R AGGAATGCGGTAGTAGTTAGGA H5a 4336T>C F AGCATTCCCCCTCAAACCTA 56 C R ATGGGCCCGATAGCTTATTT H7 4793A>G F CCGGACAATGAACCATAACC 56 C R TGATTGAGATGGGGGCTAGT H T>C F CCCACAACAAATAGCCCTTC 56 C R TGGAGTAGGGCTGAGACTGG H T>A F CCCCATGCCTCAGGATACTC 56 C R TGATTGTTAGCGGTGTGGTC H C>T F CAACATCTCCGCATGATGAA 54 C R ATTGATGAAAAGGCGGTTGA H T>C F ACATGCAGCGCAAGTAGGTC 59 C R GGGCATACAGGACTAGGAAGC H C>T F CCCTACCATGAGCCCTACAA 56 C R AATGAGGGGCATTTGGTAAA H C>T F TCATGACCCTTGGCCATAAT 56 C H G>A R ATTCGGCTATGAAGAATAGGG H C>T F ACCACAACTCAACGGCTACA 56 C R TTGTAGGGCTCATGGTAGGG H C>T F GCCTTTTACCACTCCAGCCTA 56 C R TGGTGAGCTCAGGTGATTGA H >C F CGCCACTTATCCAGTGAACC 56 C R GGAAGTATGTGCCTGCGTTC H G>C F TGACTCCCTAAAGCCCATGT 56 C R TTTTGTCAGGGGGTTGAGAA H C>T F CACCCAAGAACAGGGTTTGT 56 C H C>T R TCGTTCGGTAAGCATTAGGA H G>A F TCTTCACCAAAGAGCCCCTA 56 C R GCCTAGGTTGAGGTTGACCA F, forward, R,reverse, Tm, melting temperature.
4 4 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Table 3 Distribution of subhaplogroups of mtdna haplogroups in the LOAD patients and in the control group Subhaplogroup Whole group, n (%) Females, n (%) Males, n (%) LOAD Control group LOAD Control group LOAD Control group HV H H1 H1* 29 (6.87) 17 (5.35) 18 (6.62) 14 (6.09) 11 (7.33) 3 (3.41) H1a 2 (0.47) 2 (0.63) 2 (0.73) 0 (0.0) 0 (0.0) 2 (2.27) H1a1 3 (0.71) 3 (0.71) 2 (0.73) 3 (1.30) 1 (0.67) 0 (0.0) H1a3 0 (0.0) 3 (0.71) 0 (0.0) 2 (0.87) 0 (0.0) 1 (1.14) H1b 18 (4.26) 7 (2.20) 9 (3.31) 4 (1.74) 9 (6.0) 3 (3.41) H1c 24 (5.69) 14 (4.40) 14 (5.15) 9 (3.91) 10 (6.67) 5 (5.68) H1c1 2 (0.47) 1 (0.31) 2 (0.73) 0 (0.0) 0 (0.0) 1 (1.14) H1f 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H1k 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H2 H2* 4 (0.95) 3 (0.71) 2 (0.73) 1 (0.43) 2 (1.33) 2 (2.27) H2a1 7 (1.66) 5 (1.57) 6 (2.21) 4 (1.74) 1 (0.67) 1 (1.14) H2a2b1 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) H2a3 2 (0.47) 1 (0.31) 1 (0.37) 1 (0.43) 1 (0.67) 0 (0.0) H2a5 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) H3 H3 11 (2.61) 11 (3.46) 8 (2.94) 9 (3.91) 3 (2.0) 2 (2.27) H4 H4a 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) H4a1a1 1 (0.24) 1 (0.31) 1 (0.37) 0 (0.0) 0 (0.0) 1 (1.14) H4a1b 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H5 36 H5* 3 (0.71) 4 (1.26) 2 (0.73) 1 (0.43) 1 (0.67) 3 (3.41) H5a 20 (4.74) 8 (2.52) 13 (4.78) 8 (3.48) 7 (4.67) 0 (0.0) H36 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) H6 H6 9 (2.13) 8 (2.52) 8 (2.94) 5 (2.17) 1 (0.67) 3 (3.41) H7 H7* 3 (0.71) 3 (0.71) 2 (0.73) 2 (0.87) 1 (0.67) 1 (1.14) H7a1 1 (0.24) 2 (0.63) 0 (0.0) 2 (0.87) 1 (0.67) 0 (0.0) H7c1 1 (0.24) 1 (0.31) 0 (0.0) 1 (0.43) 1 (0.67) 0 (0.0) H8 2 (0.47) 0 (0.0) 1 (0.37) 0 (0.0) 1 (0.67) 0 (0.0) H9 H9* 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) H10 H10* 3 (0.71) 2 (0.63) 3 (1.10) 2 (0.87) 0 (0.0) 0 (0.0) H10a 0 (0.0) 2 (0.63) 0 (0.0) 1 (0.43) 0 (0.0) 1 (1.14) H11 H11* 3 (0.71) 1 (0.31) 2 (0.73) 1 (0.43) 1 (0.67) 0 (0.0) H11a 7 (1.66) 5 (1.57) 4 (1.47) 5 (2.17) 3 (2.0) 0 (0.0) H13 H13 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) H13a1 2 (0.47) 2 (0.63) 1 (0.37) 0 (0.0) 0 (0.0) 2 (2.27) H13a2 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H15 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H16 6 (1.42) 0 (0.0) 3 (1.10) 0 (0.0) 3 (2.0) 0 (0.0) H17 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) H18 2 (0.47) 3 (0.94) 1 (0.37) 2 (0.87) 1 (0.67) 1 (1.14) H21 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H24 2 (0.47) 1 (0.31) 2 (0.73) 1 (0.43) 0 (0.0) 0 (0.0) H27 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) H28 1 (0.24) 1 (0.31) 1 (0.37) 0 (0.0) 0 (0.0) 1 (1.14) H31 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) H34 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) H* 25 (5.92) 15 (4.72) 17 (6.25) 10 (4.35) 8 (5.33) 5 (5.68) HV1 HV1a1a1 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) HV1* 2 (0.47) 1 (0.31) 1 (0.37) 0 (0.0) 1 (0.67) 1 (1.14) HV0 HV0* 2 (0.47) 1 (0.31) 2 (0.73) 1 (0.43) 0 (0.0) 0 (0.0) HV0b c 3 (0.71) 1 (0.31) 1 (0.37) 1 (0.43) 2 (1.33) 0 (0.0) HV6a 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) V V* 9 (2.13) 4 (1.26) 5 (1.84) 2 (0.87) 4 (2.67) 2 (2.27) V7a 4 (0.95) 4 (1.26) 2 (0.73) 4 (1.74) 2 (1.33) 0 (0.0) IWX I I* 2 (0.47) 2 (0.63) 0 (0.0) 2 (0.87) 2 (1.33) 0 (0.0) I1 I1 1 (0.24) 2 (0.63) 1 (0.37) 2 (0.87) 0 (0.0) 0 (0.0) I1a 3 (0.71) 2 (0.63) 1 (0.37) 2 (0.87) 2 (1.33) 0 (0.0) I3 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) I4 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) W W1 W1b 2 (0.24) 0 (0.0) 2 (0.73) 0 (0.0) 0 (0.0) 0 (0.0) W1e 2 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.33) 0 (0.0) W3 W3 5 6 (1.42) 2 (0.63) 5 (1.84) 1 (0.43) 1 (0.67) 1 (1.14) W5 W5a 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.31) 0 (0.0) 0 (0.0) W6 3 (0.71) 1 (0.31) 2 (0.73) 1 (0.43) 1 (0.67) 0 (0.0)
5 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD 5 Supplementary Table 3 Subhaplogroup Whole group, n (%) Females, n (%) Males, n (%) LOAD Control group LOAD Control group LOAD Control group X X2 X2* 0 (0.0) 3 (0.94) 0 (0.0) 2 (0.87) 0 (0.0) 1 (1.14) X2b 3 (0.71) 0 (0.0) 3 (1.10) 0 (0.0) 0 (0.0) 0 (0.0) X2c 0 (0.0) 1 (0.31) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.14) JT J J1 J1* 2 (0.47) 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.33) 0 (0.0) J1b1a 3 (0.71) 8 (2.52) 2 (0.73) 4 (1.74) 1 (0.67) 4 (4.54) J1c 12 (2.84) 10 (3.14) 9 (3.31) 6 (2.61) 3 (2.0) 4 (4.54) J1c1 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) J1c1a 2 (0.47) 4 (1.26) 1 (0.37) 2 (0.87) 1 (0.67) 2 (2.27) J1c2 3 (0.71) 5 (1.57) 2 (0.73) 2 (0.87) 1 (0.67) 3 (3.41) J1c2c1 1 (0.24) 2 (0.63) 1 (0.37) 2 (0.87) 0 (0.0) 0 (0.0) J1c6 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) J1c7 2 (0.47) 1 (0.31) 1 (0.37) 0 (0.0) 1 (0.67) 1 (1.14) J2 J2a 3 (0.71) 0 (0.0) 2 (0.73) 0 (0.0) 1 (0.67) 0 (0.0) J2a1 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) J2b 2 (0.47) 1 (0.31) 0 (0.0) 1 (0.43) 2 (1.33) 0 (0.0) J2b1a 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) T T* 7 (1.66) 6 (1.89) 2 (0.73) 5 (2.17) 5 (3.33) 1 (1.14) T1 T1* 0 (0.0) 2 (0.63) 0 (0.0) 1 (0.43) 0 (0.0) 1 (1.14) T1a 7 (1.66) 8 (2.52) 2 (0.73) 7 (3.04) 5 (3.33) 1 (1.14) T2 T2* 2 (0.47) 5 (1.57) 1 (0.37) 4 (1.74) 1 (0.67) 1 (1.14) T2b 13 (3.08) 15 (4.72) 6 (2.21) 12 (5.22) 7 (4.67) 3 (3.41) T2b4 3 (0.71) 0 (0.0) 2 (0.73) 0 (0.0) 1 (0.67) 0 (0.0) T2c1b 2 (0.47) 0 (0.0) 1 (0.37) 0 (0.0) 1 (0.67) 0 (0.0) T2e 2 (0.47) 0 (0.0) 1 (0.37) 0 (0.0) 1 (0.67) 0 (0.0) T2f1 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) KU K K* 1 (0.24) 2 (0.63) 1 (0.37) 2 (0.87) 0 (0.0) 0 (0.0) K1 K1a 2 (0.47) 6 (1.89) 2 (0.73) 3 (1.30) 0 (0.0) 3 (3.41) K1a1 2 (0.47) 0 (0.0) 1 (0.37) 0 (0.0) 1 (0.67) 0 (0.0) K1a1a 0 (0.0) 4 (1.26) 0 (0.0) 2 (0.87) 0 (0.0) 2 (2.27) K1a9 0 (0.0) 2 (0.63) 0 (0.0) 2 (0.87) 0 (0.0) 0 (0.0) K1a11 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) K1b1a1 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) K1c 4 (0.95) 0 (0.0) 3 (1.10) 0 (0.0) 1 (0.67) 0 (0.0) K2 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) U U1 U1* 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U1a1 2 (0.47) 0 (0.0) 1 (0.37) 0 (0.0) 1 (0.67) 0 (0.0) U1c 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) U2 U2* 2 (0.47) 1 (0.31) 2 (0.73) 0 (0.0) 0 (0.0) 1 (1.14) U2e 9 (2.13) 1 (0.31) 4 (1.47) 1 (0.43) 5 (3.33) 0 (0.0) U2e1 3 (0.71) 1 (0.31) 3 (1.10) 1 (0.43) 1 (0.67) 0 (0.0) U3 U3* 5 (1.18) 0 (0.0) 3 (1.10) 0 (0.0) 2 (1.33) 0 (0.0) U3a 2 (0.47) 0 (0.0) 2 (0.73) 0 (0.0) 0 (0.0) 0 (0.0) U4 U4* 2 (0.47) 5 (1.57) 2 (0.73) 4 (1.74) 0 (0.0) 1 (1.14) U4a1 4 (0.95) 3 (0.94) 3 (1.10) 1 (0.43) 1 (0.67) 2 (2.27) U4a1c 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U4a2 4 (0.95) 1 (0.31) 2 (0.73) 0 (0.0) 2 (1.33) 1 (1.14) U4a2a 3 (0.71) 3 (0.94) 1 (0.37) 3 (1.30) 2 (1.33) 0 (0.0) U4a2b 0 (0.0) 2 (0.63) 0 (0.0) 2 (0.87) 0 (0.0) 0 (0.0) U4a3 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U4b1b 0 (0.0) 1 (0.31) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.14) U4c1 3 (0.71) 1 (0.31) 3 (1.10) 1 (0.43) 0 (0.0) 0 (0.0) U5 U5a 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U5a1 12 (2.84) 21 (6.60) 11 (4.04) 16 (6.96) 1 (0.67) 5 (5.68) U5a1b1 4 (0.95) 0 (0.0) 2 (0.73) 0 (0.0) 2 (1.33) 0 (0.0) U5a2 2 (0.47) 4 (1.26) 1 (0.37) 3 (1.30) 1 (0.67) 1 (1.14) U5a2a 6 (1.42) 1 (0.31) 4 (1.47) 0 (0.0) 2 (1.33) 1 (1.14) U5b 3 (0.71) 0 (0.0) 3 (1.10) 0 (0.0) 0 (0.0) 0 (0.0) U5b1a 0 (0.0) 1 (0.31) 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.14) U5b1b 5 (1.18) 1 (0.31) 3 (1.10) 1 (0.43) 2 (1.33) 0 (0.0) U5b1c 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U5b2* 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) U5b1b1a 0 (0.0) 4 (1.26) 0 (0.0) 4 (1.74) 0 (0.0) 0 (0.0)
6 6 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Table 3 Subhaplogroup Whole group, n (%) Females, n (%) Males, n (%) LOAD Control group LOAD Control group LOAD Control group U5b2a1 0 (0.0) 4 (0.94) 0 (0.0) 2 (0.87) 0 (0.0) 2 (2.27) U5b2a2 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) U5b2c 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) U7 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) U8 U8a1 2 (0.47) 2 (0.63) 1 (0.37) 1 (0.43) 1 (0.67) 1 (1.14) U8b 0 (0.0) 2 (0.63) 0 (0.0) 2 (0.87) 0 (0.0) 0 (0.0) N N1 N1a 1 (0.24) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) N1a1 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) N1b 4 (0.95) 3 (0.94) 3 (1.10) 2 (0.87) 1 (0.67) 1 (1.14) Y Y1b 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) A A8 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) R* R2 R2* 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) R0 R0a 0 (0.0) 1 (0.31) 0 (0.0) 1 (0.43) 0 (0.0) 0 (0.0) M C C* 1 (0.24) 0 (0.0) 1 (0.37) 0 (0.0) 0 (0.0) 0 (0.0) D D4/G 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) M37 M37a 1 (0.24) 1 (0.31) 1 (0.37) 1 (0.43) 0 (0.0) 0 (0.0) L2 1 (0.24) 1 (0.31) 0 (0.0) 0 (0.0) 1 (0.67) 0 (0.0) Unclassified 0 (0.0) 4 (1.26) 0 (0.0) 3 (1.30) 0 (0.0) 0 (0.0) Supplementary Table 4 Odds ratios of LOAD, when the individuals that do not carry H5 subhaplogroup or APOE4 are the reference group (OR = 1) H5 APOE4 Control LOAD OR subhaplogroup status group, n patients, n Supplementary Table 5 Odds ratios for LOAD with aggregated mitochondrial haplogroups and subhaplogroups harboring variants in CYTB and/or ATP6. Statistical analysis was performed using χ 2 test or Fisher s exact test Aggregated mtdna haplogroups Whole group Females Males and subhaplogroups OR 95% CI p OR 95% CI p OR 95% CI p U4 + U5a1 + K U4+U5a1+K+J U4+U5a1+K+J1c U4+U5a1+K+J1c+J U4 + U5a1 + K+J1c+J2 + T U4+U5a1+K+J+T UKJT Supplementary Table 6 Nucleotide substitutions in the mtdna control region of LOAD patients and the control group as compared with revised Cambridge Reference Sequence Nucleotide Nucleotide Locus LOAD Control position in mtdna change patients, n individuals, n 3 T>C 7S DNA T>C 7S DNA T>C 7S DNA, HVSII T>C 7S DNA, HVSII C>T 7S DNA, HVSII T>C 7S DNA, HVSII A>G 7S DNA, HVSII T>C 7S DNA, HVSII A>G 7S DNA, HVSII A>C 7S DNA, HVSII 1 0
7 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD 7 Supplementary Table 6 Nucleotide Nucleotide Locus LOAD Control position in mtdna change patients, n individuals, n 114 C>T 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII G>A 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII C>T 7S DNA, OH, HVSII C>T 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII A>G 7S DNA, OH, HVSII G>A 7S DNA, OH, HVSII C>A 7S DNA, OH, HVSII A>G 7S DNA, OH, HVSII A>G 7S DNA, OH, HVSII A>G 7S DNA, OH, HVSII C>T 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII C>T 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII A>G 7S DNA, OH, HVSII G>A 7S DNA, OH, HVSII T>C 7S DNA, OH, HVSII G>A OH, HVSII A>G OH, HVSII A>G OH, HVSII A>G OH, CSB1, HVSII A>G OH, CSB1, HVSII T>C OH, CSB1, HVSII C>T OH, CSB1, HVSII G>A OH, CSB1, HVSII T>C OH, CSB1, HVSII A>G OH, CSB1, HVSII G>A OH, CSB1, HVSII A>G OH, CSB1, HVSII T>C OH, HVSII T>C OH, TFX, HVSII A>G OH, TFX, HVSII C>T OH, TFX, HVSII G>A OH, TFX, HVSII A>G OH, TFX, HVSII A>G OH, TFX, HVSII T>C OH, TFX, HVSII T>C OH, TFX, HVSII A>G OH, TFX, HVSII A>G OH, TFX, HVSII C>T OH, TFX, HVSII A>G OH, TFX, HVSII T>C OH, TFY, HVSII T>C OH, TFY, HVSII C>T OH, TFY, HVSII A>G OH, TFY, HVSII T>C OH, TFY, HVSII T>C OH, TFY, HVSII C>T OH, TFY, HVSII C>A OH, TFY, HVSII A>G OH, TFY, HVSII T>C OH, TFY, HVSII G>A OH, TFY, HVSII T>C OH, TFY, HVSII A>G OH, TFY, HVSII 0 1
8 8 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Table 6 Nucleotide Nucleotide Locus LOAD Control position in mtdna change patients, n individuals, n 338 C>T OH, TFY, HVSII C>T OH, TFY, HVSII A>G OH, mt4h, HVSII A>G OH, mt3h, HVSII T>C OH, PL, HVSII, mttf1 binding site C>T HVSIII C>T HVSIII C>T HVSIII T>C HVSIII T>C HVSIII T>C HVSIII C>T HVSIII G>A HVSIII T>C HVSIII A>G HVSIII G>A HVSIII A>G HVSIII C>T HVSIII A>G HVSIII, mttf1 binding site A>G HVSIII, mttf1 binding site C>T HVSIII, PH A>G HVSI A>G HVSI C>T HVSI C>T HVSI A>G HVSI C>T HVSI T>C HVSI A>G HVSI T>C HVSI T>A HVSI T>C HVSI C>T HVSI C>T 7S DNA, HVSI C>G 7S DNA, HVSI C>T 7S DNA, HVSI A>C 7S DNA, HVSI C>A 7S DNA, HVSI C>G 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI G>A 7S DNA, HVSI G>C 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI G>A 7S DNA, HVSI A>G 7S DNA, HVSI C>A 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI G>A 7S DNA, HVSI T>C 7S DNA, TAS, HVSI A>G 7S DNA, TAS, HVSI A>G 7S DNA, TAS, HVSI A>G 7S DNA, TAS, HVSI C>T 7S DNA, TAS, HVSI C>T 7S DNA, TAS, HVSI C>T 7S DNA, TAS, HVSI 0 1
9 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD 9 Supplementary Table 6 Nucleotide Nucleotide Locus LOAD Control position in mtdna change patients, n individuals, n T>C 7S DNA, TAS, HVSI C>T 7S DNA, HVSI C>A 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI A>C 7S DNA, HVSI A>C 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI C>G 7S DNA, HVSI C>T 7S DNA, HVSI T>A 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, mt5, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI A>G 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI A>T 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI G>A 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>A 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI G>A 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI C>A 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI 1 1
10 10 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Table 6 Nucleotide Nucleotide Locus LOAD Control position in mtdna change patients, n individuals, n C>T 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI C>A 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI A>G 7S DNA, HVSI A>G 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI G>A 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI A>T 7S DNA, HVSI G>A 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI A>G 7S DNA, HVSI T>C 7S DNA, HVSI A>G 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI T>C 7S DNA, HVSI C>T 7S DNA, HVSI G>A 7S DNA G>A 7S DNA G>A 7S DNA A>G 7S DNA C>T 7S DNA G>A 7S DNA C>T 7S DNA A>G 7S DNA G>A 7S DNA A>G 7S DNA T>C 7S DNA G>A 7S DNA C>T 7S DNA 1 2 HVSI-III- hypervariable segment I-III; TFX, TFY - mttf1 binding sites; mttf1 - mitochondrial transcription factor; OH - H-strand origin; CSB1 3 - Conserved sequence block 1 3; mt3h, mt4h, mt5h regulatory elements on H-strand; PL L-strand promoter; TAS termination associated sequence; PH1 Major H-strand promoter.
11 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD 11 Supplementary Table 7 Distribution of deletions and insertions detected in mtdna control region of LOAD patients and the control group LOAD patients, n Control group, n Deletions 249D D D D D 1 0 Insertions 42.1G C C C T C T C 523.2A nC 18 9 Supplementary Table 8 Single nucleotide heteroplasmic substitutions detected in the mitochondrial control region of LOAD patients and in the control group Heteroplasmic LOAD Control substitution patients, n group, n m.152t/c 3 0 m.195t/c 0 0 m.204t/c 2 1 m.310c/t 1 1 m.497c/t 0 0 m.499g/a 0 1 m.16093c/t 1 0 m.16129g/a 0 0 m.16183c/a 1 0 m.16189c/t 2 0 m.16192c/t 1 1 m.16193c/t 0 1 m.16291c/t 1 0 m.16294c/t 0 1 m.16301c/t 0 1 m.16519t/c 0 0 Supplementary Table 9 Variants in the mitochondrial control region not described in MITOMAP and Human Mitochondrial Genome database Variant LOAD Control Haplogroup, Locus APOE Variant patients, n group, n subhaplogroup m.203g>c 1 0 H2 HVSII, OH 33 m.273c>t 1 0 H6 OH, TFY, HVSII 34 m.299d 1 0 H6 CSB2, TFY, HVSII 34 m.16474g>t 1 0 K1c 33 m.16290c>g 1 0 A8 HVSI, 7S DNA 33 m.16213g>c 1 0 H1c HVSI, 7S DNA 44 m.16078a>c 1 0 U3 HVSI 44 m.490.1c 0 1 J1c HVSIII 33 m.42.1g 0 1 H11 7S DNA 33 m.16179c>g 0 1 J1c 7S DNA, HVSI 24 D- deletion; F- female, M- male; HVSI-III- hypervariable segment I-III; TFY - mttf1 binding site, OH - H-strand origin; CSB2 - Conserved sequence block 2.
12 12 A. Maruszak et al. / Mitochondrial and Nuclear DNA Variants in LOAD Supplementary Table 10 Odds ratios for LOAD risk associated with the variants m.217t>c, m.242c>t, m.497c>t, m.16126t>c, m.16343a>g, m.16129g>c and m.16224t>c. Statistical analysis was performed using Fisher s exact test and multivariate logistic regression controlling for APOE4 status, AAO/age and gender Control region Univariate analysis Multivariate logistic regression polymorphism p OR 95% CI p OR 95% CI m.217t>c m.242c>t m.497c>t m.16126t>c m.16343a>g n.a. n.a. n.a. m.16129g>c m.16224t>c Supplementary Table 11 Testing balanced accuracy and cross validation consistency for the best MDR models for the prediction of LOAD risk with one to four loci # of loci Model Testing Cross Validation p Balanced Accuracy Consistency (CVC) 1 APOE4 status / APOE4 status rs / APOE4 status rs1937 rs / APOE4 status rs1937 rs U5b / Supplementary Table 12 Multivariate logistic regression for LOAD including APOE4 status, rs1937, subhaplogroup H5, gender, AAO/age and interactions H5 APOE4 status, rs1937 APOE4 status and rs1937 haplogroup H5 Covariates p OR 95% CI APOE4 status H5 subhaplogroup rs1937 genotype APOE4 status H rs1937 APOE4 status rs1937 H AAO/age < gender
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