Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes

Jonas Bybjerg-Grauholm; Christian M. Hagen; Vanessa F. Gonçalves; Marie Bækvad-Hansen; Christine S. Hansen; Paula L. Hedley; Jørgen K. Kanters; Jimmi Nielsen; Michael Theisen; Ole Mors; James Kennedy; Thomas D. Als; Alfonso B. Demur; Merete Nordentoft; Anders Børglum; Preben B. Mortensen; Thomas M. Werge; David M. Hougaard; Michael Christiansen

doi:10.1371/journal.pone.0208829

Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes

Jonas Bybjerg-Grauholm, Christian M. Hagen, Vanessa F. Gonçalves, Marie Bækvad-Hansen, Christine S. Hansen, Paula L. Hedley, Jørgen K. Kanters, Jimmi Nielsen, Michael Theisen, Ole Mors, James Kennedy, Thomas D. Als, Alfonso B. Demur, Merete Nordentoft, Anders Børglum, Preben B. Mortensen, Thomas M. Werge, David M. Hougaard, Michael Christiansen^*

^*Corresponding author af dette arbejde

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Abstract

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.

Originalsprog	Engelsk
Artikelnummer	e0208829
Tidsskrift	PLoS ONE
Vol/bind	13
Udgave nummer	12
Antal sider	26
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0208829
Status	Udgivet - 13 dec. 2018

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10.1371/journal.pone.0208829Licens: CC BY

journal.pone.0208829Forlagets udgivne version, 2,87 MBLicens: CC BY

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Bybjerg-Grauholm, J., Hagen, C. M., Gonçalves, V. F., Bækvad-Hansen, M., Hansen, C. S., Hedley, P. L., Kanters, J. K., Nielsen, J., Theisen, M., Mors, O., Kennedy, J., Als, T. D., Demur, A. B., Nordentoft, M., Børglum, A., Mortensen, P. B., Werge, T. M., Hougaard, D. M., & Christiansen, M. (2018). Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes. PLoS ONE, 13(12), Artikel e0208829. https://doi.org/10.1371/journal.pone.0208829

Bybjerg-Grauholm, J, Hagen, CM, Gonçalves, VF, Bækvad-Hansen, M, Hansen, CS, Hedley, PL, Kanters, JK, Nielsen, J, Theisen, M, Mors, O, Kennedy, J, Als, TD, Demur, AB, Nordentoft, M, Børglum, A, Mortensen, PB, Werge, TM, Hougaard, DM & Christiansen, M 2018, 'Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes', PLoS ONE, bind 13, nr. 12, e0208829. https://doi.org/10.1371/journal.pone.0208829

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title = "Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes",

abstract = "Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.",

author = "Jonas Bybjerg-Grauholm and Hagen, {Christian M.} and Gon{\c c}alves, {Vanessa F.} and Marie B{\ae}kvad-Hansen and Hansen, {Christine S.} and Hedley, {Paula L.} and Kanters, {J{\o}rgen K.} and Jimmi Nielsen and Michael Theisen and Ole Mors and James Kennedy and Als, {Thomas D.} and Demur, {Alfonso B.} and Merete Nordentoft and Anders B{\o}rglum and Mortensen, {Preben B.} and Werge, {Thomas M.} and Hougaard, {David M.} and Michael Christiansen",

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AU - Bybjerg-Grauholm, Jonas

AU - Hagen, Christian M.

AU - Gonçalves, Vanessa F.

AU - Bækvad-Hansen, Marie

AU - Hansen, Christine S.

AU - Hedley, Paula L.

AU - Kanters, Jørgen K.

AU - Nielsen, Jimmi

AU - Theisen, Michael

AU - Mors, Ole

AU - Kennedy, James

AU - Als, Thomas D.

AU - Demur, Alfonso B.

AU - Nordentoft, Merete

AU - Børglum, Anders

AU - Mortensen, Preben B.

AU - Werge, Thomas M.

AU - Hougaard, David M.

AU - Christiansen, Michael

PY - 2018/12/13

Y1 - 2018/12/13

N2 - Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.

AB - Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.

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Complex spatio-temporal distribution and genomic ancestry of mitochondrial DNA haplogroups in 24,216 Danes

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