Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). This bi-genomic linkage disequilibrium (2GLD) could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The extensive 2GLD documented is a major concern when interpreting historic as well as designing future mtDNA association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/149070 doi: bioRxiv preprint first posted online 3 Genetic variants in mitochondrial DNA (mtDNA) -and in nuclear genes coding for mitochondrial function -have been associated with disease 1-3 . More than 300 variants 4,5 in mtDNA and genes involved in mitochondrial function 6 have been reported to cause mitochondrial disease which is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms 7,8 .SNPs in mtDNA and mitochondrial haplogroups (mtDNA hgs), which are evolutionarily fixed SNP sets with a characteristic geographical distribution, have been proposed as potential disease modifiers 8 . This has been reported in neurological degenerative diseases such as Alzheimer's disease 9-12 and Parkinson's disease 12-14 , metabolic diseases and cancers 15 , as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease [16][17][18] .Association studies of mtDNA variants and disease have been difficult to replicate 8 . However, the definition of a methodological paradigm for association studies with mtDNA variants 19 implicitly assumes that mtDNA variants are independent of the nuclear genome. In a recent Danish study on mtDNA haplogroups and their nuclear ancestry or nuclear genogeographical affinity (GGA), we demonstrated a marked difference in nuclear ancestry between individual haplogroups 20 . This means that mtDNA hgs entail population stratification also at the level of gDNA. The effect of such a stratification on disease association, will depend on the admixture structure of the particular population, the population history, epidemiology and genetic epidemiology of the disease, as well as the number of persons included in the study. The extensive fine-scale heterogeneity of gDNA and significant admixture documented in the UK 21 and Europe 22 further increase the risk of spurious false positive associations, if the mtDNA/gDNA interaction is not corrected phenomenon for in association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The co...