Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants.
Isolated populations are emerging as a powerful study design in the search for low-frequency and rare variant associations with complex phenotypes. Here we genotype 2,296 samples from two isolated Greek populations, the Pomak villages (HELIC-Pomak) in the North of Greece and the Mylopotamos villages (HELIC-MANOLIS) in Crete. We compare their genomic characteristics to the general Greek population and establish them as genetic isolates. In the MANOLIS cohort, we observe an enrichment of missense variants among the variants that have drifted up in frequency by more than fivefold. In the Pomak cohort, we find novel associations at variants on chr11p15.4 showing large allele frequency increases (from 0.2% in the general Greek population to 4.6% in the isolate) with haematological traits, for example, with mean corpuscular volume (rs7116019, P=2.3 × 10(-26)). We replicate this association in a second set of Pomak samples (combined P=2.0 × 10(-36)). We demonstrate significant power gains in detecting medical trait associations.
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Kalliope
K
Panoutsopoulou
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Konstantinos
K
Hatzikotoulas
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
Dionysia Kiara
DK
Xifara
Institute of Genetics and Biophysics 'A. Buzzati-Traverso', National Research Council (CNR), Naples 80131, Italy.
Vincenza
V
Colonna
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 17671, Greece.
Aliki-Eleni
AE
Farmaki
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.
Graham R S
GR
Ritchie
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Lorraine
L
Southam
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Arthur
A
Gilly
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Ioanna
I
Tachmazidou
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] H3Africa Bioinformatics Network (H3ABioNet) Node, National Biotechnology Development Agency (NABDA), Federal Ministry of Science and Technology (FMST), Abuja 900107, Nigeria [3] International Health Research Group, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8NR, UK.
Segun
S
Fatumo
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Angela
A
Matchan
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [3] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Nigel W
NW
Rayner
1] Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 17671, Greece [2] Department of Health Sciences, University of Leicester, Leicester LE1 7RH, UK.
Ioanna
I
Ntalla
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] Division of Medical Genetics, Department of Reproductive Sciences and Development, IRCCS-Burlo Garofolo, University of Trieste, Trieste 34137, Italy.
Massimo
M
Mezzavilla
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Yuan
Y
Chen
Anogia Medical Centre, Anogia 74051, Greece.
Chrysoula
C
Kiagiadaki
1] Dromokaiteio Psychiatric Hospital of Athens, Chaidari, Athens 12461, Greece [2] Department of Human Metabolism, University of Sheffield, Sheffield S10 2TN, UK.
Eleni
E
Zengini
1] Dromokaiteio Psychiatric Hospital of Athens, Chaidari, Athens 12461, Greece [2] School of Medicine, National and Kapodistrian University of Athens, Goudi, Athens 11527, Greece.
Vasiliki
V
Mamakou
Echinos Medical Centre, Xanthi 67300, Greece.
Antonis
A
Athanasiadis
School of Health Sciences, Faculty of Nursing, National and Kapodistrian University of Athens, Goudi, Athens 11527, Greece.
Margarita
M
Giannakopoulou
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 17671, Greece.
Vassiliki-Eirini
VE
Kariakli
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, PO Box 49, Entebbe, Uganda.
Rebecca N
RN
Nsubuga
Medical Research Council/Uganda Virus Research Institute, Uganda Research Unit on AIDS, PO Box 49, Entebbe, Uganda.
Alex
A
Karabarinde
1] Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK [2] International Health Research Group, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8NR, UK.
Manjinder
M
Sandhu
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Gil
G
McVean
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Chris
C
Tyler-Smith
Anogia Medical Centre, Anogia 74051, Greece.
Emmanouil
E
Tsafantakis
Echinos Medical Centre, Xanthi 67300, Greece.
Maria
M
Karaleftheri
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Yali
Y
Xue
Department of Nutrition and Dietetics, Harokopio University of Athens, Athens 17671, Greece.
George
G
Dedoussis
Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton CB10 1HH, UK.
Eleftheria
E
Zeggini
D000293:Adolescent; D001773:Blood Cells / Q000166:cytology; D048429:Cell Size; D015331:Cohort Studies; D005787:Gene Frequency / Q000235:genetics; D040961:Genetic Drift; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006115:Greece; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D011153:Population / Q000235:genetics*; D012934:Social Isolation