Genome-wide association studies of complex traits have been successful in identifying common variant associations, but a substantial heritability gap remains. The field of complex trait genetics is shifting towards the study of low-frequency and rare variants, which are hypothesised to have larger effects. The study of these variants can be empowered by focusing on isolated populations, in which rare variants may have increased in frequency and linkage disequilibrium tends to be extended.

With our collaborators at Harokopio University in Athens, we are investigating the effects of such genetic variants in two isolated populations in Greece. The HELIC cohort collection, including biological samples and extensive phenotype data, started in 2009. We aim to investigate the association of low-frequency and rare variants with complex traits of medical relevance employing whole-genome sequencing approaches.

The HELIC work focuses on two isolated populations, each with information on a wide array of anthropometric, cardiometabolic, biochemical, haematological and diet-related traits.

• The MANOLIS sub-study (Minoan Isolates) focuses on a set of mountainous villages (Mylopotamos villages) on the island of Crete, Greece.

This programme of work is named MANOLIS to honour the memory of Manolis Giannakakis, 1978-2010.

• The Pomak villages are a set of isolated mountainous villages in the North of Greece.

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Png G, Barysenka A, Repetto L, et al. Mapping the serum proteome to neurological diseases using whole genome sequencing. Nat Commun 2021, 12:7042. PMID: 34857772

Gilly A, Park Y-C, Png G, et al.Whole-genome sequencing analysis of the cardiometabolic proteome.Nat Commun 2020, 11: 6336. PMID: 33303764

Farmaki A-E, Rayner W, Gilly A, et al.  A Dietary Pattern with High Sugar Content is Associated with Cardiometabolic Risk Factors in the Pomak Population. Nutrients. 2019 Dec 11(12):3043 PMID: 31847144

Gilly A, Southam L, Süveges, et al. Very low-depth whole-genome sequencing in complex trait association studies. Bioinformatics. 2019 Aug 1;35(15):2555-2561. PMID: 30576415 

Zheng J, Maerz W, Gergei I, et al. Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures. J Bone Miner Res. 2019 Jun 6 10.1002 PMID:31170332

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Haworth S, Shapland CY, Hayward C, et al. Low-frequency variation in TP53 has large effects on head circumference and intracranial volume. Nat Commun Jan 2019;10:357. PMID:3064637

Hackinger S, Prins B, Mamakou V, et al. Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia. Transl Psychiatry. 2018 Nov 23;8(1):252. PMID:30470734

Gilly A, Süveges D, Kuchenbaecker K, et al. Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits. Nat Commun. 2018 Nov 7;9(1):4674.PMID: 30568165

Grarup N, Moltke I, Anderson MK, et al. Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nat Commun Feb 2018;10:357. PMID: 29311636

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Southam L, Gilly A, Süveges D, et al. Whole genome sequencing and imputation in isolated populations identify genetic associations with medically-relevant complex traits. Nat Commun 2017, May 26;8:15606. PMID:28548082 

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Surendran P, Drenos F, Young R, et al. Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nat Genet. 2016 Oct;48(10):1151-61. PMID:27618447.

Gilly A, Ritchie GR, Southam L, et al. Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation. Hum Mol Genet. 2016, PMID:27146844. 

Zeggini E, Gloyn AL, Hansen T, et al. Insights into metabolic disease from studying genetics in isolated populations: stories from Greece to Greenland. Diabetologia 2016, 5:938-41. PMID:26993633.

Kanoni S, Masca NGD, Stirrups KE, et al. Analysis with the exome array identifies multiple new independent variants in lipid loci Hum Mol Genet. (2016) 25 (18): 4094-4106. PMID:27466198.

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Sidore C, Busonero F, Maschio A, et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet. 2015 47(11):1272-81. PMID: 26366554. 

Winkler TW, Justice AE, Graff M, et al. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet. 2015 11(10) PMID: 27355579. 

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Joshi PK, Esko T, Mattsson H, et al. Directional dominance on stature and cognition in diverse human populations. Nature 2015 523(7561):459-62. PMID:26131930. 

Wessel J, Chu AY, Willems SM, et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat Commun. 2015 6:5897. PMID: 25631608 

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Panoutsopoulou K, Hatzikotoulas K, Xifara DK,et al. Genetic characterization of Greek population isolates reveals strong genetic drift at missense and trait-associated variants. Nat Commun 2014, 5:5345.PMID: 25373335.   

Timpson NJ, Walter K, Min JL, et al. A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans. Nat Commun. 2014 Sep 16;5:4871.PMID: 25225788

Tachmazidou I, Dedoussis G, Southam L, et al. A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates. Nat Commun 2013, 4:2872. PMID: 24343240   

Gilly A, Deep whole-genome sequencing and the genetic architecture of the cardiometabolic proteome. Presented at Olink Symposium Harvard 2019

Png G, Suveges D, Park YP, et al Fast calling of copy number variants from population scale high-depth whole genome sequencing. Presented at ASHG 2018, IGES 2018 and Olink Symposium Würzburg 2018

Arthur Gilly, Daniel Suveges, Karoline Kuchenbaecker, et al. Population-wide whole-genome sequencing in a founder population reveals rare variant burdens associated with multiple quantitative traits ASHG 2017

Arthur Gilly, Daniel Suveges, Karoline Kuchenbaecker, et al. Population-wide whole-genome sequencing in an isolated cohort reveals rare variant burdens associated with multiple quantitative traits Presented at The 2017 Annual Meeting of the International Genetic Epidemiology Society

Gilly A, Southam L, Moore R, et al. How low can you go: cohort-wide 1x whole genome sequencing in a Greek isolate reveals multiple quantitative trait signals. (platform presentation) Presented at ASHG 2015.

Zeggini E, Farmaki A-E, Hatzikotoulas K, Tachmazidou I. Town Hall meetings. (platform presentation) Zoniana and Anogia, Crete, Greece, August 2014.

Gilly A, Schwartzentruber J, Matchan A, et al. Robust genotype calling from very low depth whole genome sequencing data. (platform presentation) Presented at IGES 2014.

Tachmazidou I, Southam L, Farmaki A-E, et al. Next generation association studies in isolated populations. (poster) Presented at Biology of Genomes 2013 and IGES 2013.

Panoutsopoulou K, Tachmazidou I, Farmaki A-E, et al. Powerful detection of rare variant associations using Hellenic population isolates. (platform presentation) Presented at Genomics Medicine in the Mediterranean 2013.

Hatzikotoulas K, Panoutsopoulou K, Farmaki A-E, et al. Genetic characterisation of two Greek population isolates. (poster) Presented at ASHG 2013.

Matchan A, Rayner NW, Farmaki A-E, et al. How to reduce false positives: A quality assurance pipeline for phenotype data. (poster) Presented at ASHG 2013

Zeggini E, Dedoussis G, Southam L, et al. A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates. (platform presentation) Presented at ASHG 2013.

See Genetics of Osteoarthritis consortium website