Our research leverages big data in genetics and genomics for medically important human traits. We aim to translate insights from genomics into mechanisms of disease development and progression, shortening the path to translation and empowering precision medicine.
Our overarching aims are to
- Characterise the genetic architecture of common complex diseases of high public health burden;
- Generate insights into the biological mechanisms underpinning chronic disease development and progression;
- Develop robust methods for integrating big data to address key biomedical challenges;
- Catalyse pathways to translation for disease prognosis, management and treatment.
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.
Gilly A, Klaric L, Park YC, et al.Gene-based whole genome sequencing meta-analysis of 250 circulating proteins in three isolated European populations. Mol Metab 2022, 61: 101509. PMID: 35504531
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
Justice AE, Karaderi T, Highland HM, et al. Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics 2019 Mar;50:172-4. PMID:30778226
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
Xue Y, Mezzavilla M, Haber M, et al. Enrichment of low frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. Nat Commun 2017 Jun 23;8:5927. PMID: 28643794
Farmaki AE, Rayner NW, Matchan A, et al. The mountainous Cretan dietary patterns and their relationship with cardiovascular risk factors: The Hellenic Isolated Cohorts Manolis Study. Public Health Nutr.2017 Apr;20(6):0631074.PMID: 27989266
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
Marouli E, Graff M, Medina-Gomez C, et al. Rare and low-frequency coding variants alter human adult height. Nature. 2017 Feb 9;542(7640):186-190. PMID: 28146470.
Van den Berg ME, Warren HR, Cabrera CP, et al. Discovery of novel heart rate-associated loci using the Exome Chip. Hum Mol Genet. 2017 Apr 3, 10.1093. PMID: 28379579.
Ried JS, Jeff M J, Chu AY, et al. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. Nat Commun. 2016 Nov 23;7:13357. PMID: 27876822.
Lotchkova V, Huang J, Morris JA, et al. Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps. Nat Genet. 2016 Nov;48(11):1303-1312. PMID: 27668658.
McCarthy S, Das S, Kretzschmar W, et al A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet. 2016 Oct;48(10):1279-83. PMID: 27548312.
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.
Zoledziewska M, Sidore C, Chiang CW, et al. Height-reducing variants and selection for short stature in Sardinia. Nat Genet. 2015 47(11):1352-6. PMID: 26366551.
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.
UK10K Consortium, Walter K, Min JL, HuangJ, et al. The UK10K project identifies rare variants in health and disease. Nature 2015 526(7571):82-90. PMID:26367797.
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
Hatzikotoulas K, Gilly A and Zeggini E, et al. Using population isolates in genetic association studies Brief Funct Genomics. (2014) 13 (5): 371-377. PMID: 25009120.
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.
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
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.
Selected PublicationsSee all
2019 Nature Genetics