Alexandra (Sasha) Zhernakova, MD, PhD
Rosalind Franklin Fellow & ERC Starting grant holder
My research team works on understanding the role of various genetic and environmental factors in the predisposition to common diseases and traits, including gastrointestinal and autoimmune diseases, and ageing. We are also focusing on the composition of the gut microbiome, the factors that shape the microbiome -including genetics, diet, medication and other environmental factors-, and the role of the microbiome in gut health and common diseases.
In Sept. 2016 I was awarded an ERC Starting grant to study “ The role of the virome in shaping the gut ecosystem during the first year of life” and since 2012 I have held a Rosalind Franklin Fellowship from the University of Groningen.
My group has three main research lines:
1. Investigating host and environmental factors that shape the human microbiome and understanding its role in relation to human diseases and aging
-The role of the virome in shaping the gut ecosystem during the first year of life
In this ERC-funded project we are studying the development of gut flora in newborns. At birth, babies have a limited number of bacteria and viruses in their guts. These increase during the first twelve months, eventually forming a stable colony of gut flora (the microbiome). We are trying to discover how the viruses and bacteria develop and how this affects babies’ health. We will study both genetic factors and environmental factors, such as diet, vaccinations and disease. Data from LifeLines-Next, a project that is collecting samples and information from 1,500 babies during their first year of life will be used in this research.
-Other work has included sequencing and analysing the gut microbiome in a unique, well-phenotyped cohort of 1,500 individuals (LifeLines-Deep, see Tigchelaar et al. BMJ open 2015) – currently the largest such cohort available. We found a strong link of microbiota with several human phenotypes and have shown a link between the microbiome and lipid metabolism (Fu et al. Circulation Research 2015; awarded the Best Paper prize by Circulation Research in 2015).
-We have further shown strong effects in stool consistency from the gut microbiome (Tigchelaar et al. Gut 2015), medication (Imhann et al. Gut, 2015), genetic composition (in progress), diet (Bonder et al. Genome Medicine, 2016) and from over 100 other intrinsic and environmental factors (Zhernakova et al. Science, 2016; Falony et al. Science, 2016; news). We are currently investigating the relationship between the intestinal bacteria, genetics and gut-related diseases (inflammatory bowel disease and irritable bowel syndrome).
Zhernakova A, Kurilshikov A, Bonder MJ, ... Xavier RJ, Wijmenga C, Fu J. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity Science, 2016.
Bonder MJ, Tigchelaar EF, Cai X, Trynka G, Cenit MC, Hrdlickova B, ... Wijmenga C, Wang Y, Zhernakova A. The influence of a short-term gluten-free diet on the human gut microbiome Genome Med. 2016.
Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, Tigchelaar EF, Jankipersadsing SA, Cenit MC, ... Franke L, Xavier RJ, Jonkers D, Wijmenga C, Weersma RK, Zhernakova A. Proton pump inhibitors affect the gut microbiome Gut. 2015.
Fu J, Bonder MJ, Cenit MC, Tigchelaar EF, Maatman A, Dekens JA, Brandsma E, Marczynska J, Imhann F, Weersma RK, Franke L, Poon TW, Xavier RJ, Gevers D, Hofker MH, Wijmenga C, Zhernakova A. The gut microbiome contributes to a substantial proportion of the variation in blood lipids Circ Res. 2015.
2. Systemic analysis of age-related changes in humans
My group participated in the analysis of gene-expression changes with ageing, performed in collaboration with the CHARGE consortium, which has identified massive age-related changes in expression profiles. These have been followed up by functional studies (Peters et al. Nature Methods 2015). Analysis of methylation profiles allowed us to estimate methylation ageing, which more accurately reflects biological ageing, compared to telomeres and other established markers of senescence (Shah et al. AJHG 2015, and ongoing work). We are currently measuring the telomere length in different cell types in 1,500 individuals from the LifeLines cohort, and linking these results with other measurements of biological ageing, including markers of thymus involution, age-related changes in microbiome composition, and more.
Peters MJ, Joehanes R, Pilling LC, ... Zhernakova A, ... Franke L, ... Johnson AD. The transcriptional landscape of age in human peripheral blood. Nat Commun. 2015.
Shah S, Bonder MJ, ... Zhernakova A, ... Franke L, Deary IJ, Visscher PM. Improving phenotypic prediction by combining genetic and epigenetic associations. Am J Hum Genet. 2015.
3. Fine-mapping of HLA locus in relation to immune diseases and aging
HLA is an extensived locus that includes hundreds of immune-related genes. It is associated with the majority of immune and infectious diseases and is characterized by strong signs of selection. We are fine-mapping the HLA locus and looking for the effect of various HLA alleles in the predisposition to autoimmune diseases, infections and microbiome composition (Gutierrez-Achury et al. Nature Genetics, 2015). We are also looking at the functional consequences of HLA alleles and haplotypes via allele-specific regulation of gene expression and methylation.
Gutierrez-Achury J, Zhernakova A, Pulit SL, Trynka G, Hunt KA, Romanos J, Raychaudhuri S, van Heel DA, Wijmenga C, de Bakker PI. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nat Genet. 2015.
Gutierrez-Achury J, Zorro MM, Ricaño-Ponce I, Zhernakova DV, Coeliac Disease Immunochip consortium, RACI consortium, Diogo D, Raychaudhuri S, Franke L, Trynka G, Wijmenga C, Zhernakova A. Functional implications of disease-specific variants in loci jointly associated to coeliac disease and rheumatoid arthritis. Hum Mol Genet. 2015.
Franke L, El Bannoudi H, Jansen DT, Kok K, Trynka G, Diogo D, Swertz M, Fransen K, Knevel R, Gutierrez-Achury J, Ärlestig L, Greenberg JD, Kremer J, Pappas DA, Kanterakis A, Weersma RK, van der Helm-van Mil AH, Guryev V, Rantapää-Dahlqvist S, Gregersen PK, Plenge RM, Wijmenga C, Huizinga TW, Ioan-Facsinay A, Toes RE, Zhernakova A. Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes. Eur J Hum Genet. 2015.
Postdoc: Alexander Kurilshikov
PhD students: Marc Jan Bonder, Ettje Tigchelaar, Soesma Medema-Jankipersadsing
Technician: Jody Arends
Postdocs: Jingyuan Fu, Maria Carmen Cenit
PhD students: Javier Gutierrez-Achury (PhD thesis, 2015 "HLA and other tales: The different perspectives of Celiac Disease")
Co-supervised PhD students (short-term projects): Aurora Serrano, Joanna Marczynska
MSc student internships: Anastassia Blanter, Kees Neerdeveer, Debbie van Dussen, Janneke Pietersma
Summary of past research
I gained my medical degree in paediatrics and worked as a consultant paediatrician at the Centre for Medical Genetics in St. Petersburg, Russia (1998–2000). In 2000, I moved to the Netherlands and started my research career doing volunteer work in the Department of Biomedical Genetics, UMC Utrecht, followed by a position as a research technician and then a PhD position.
My PhD research (2005–2009) focused on determining the genetic predisposition to immune-related diseases. I performed several large-scale genetic and genomic studies and identified susceptibility loci for coeliac disease, inflammatory bowel disease, rheumatoid arthritis, and other immune-related diseases. My research also included pathway analyses, gene expression analyses, linkage analyses, functional studies, and the evolutionary analyses of associated loci. This work led to the key concept of the shared genetic basis for immune diseases, which was described in a Nature Review Genetics article (Zhernakova et al. 2009), and many other research papers. (PhD thesis, 2009 "The autoimmune puzzle - shared and specific genetics of immune-related diseases")
For my postdoctoral research (2010-2011), I continued to work on the shared genetics of autoimmune diseases and the functional implications, first in one of the leading groups on rheumatoid arthritis (Plenge lab, Harvard Medical School, Boston, on my NWO Rubicon grant) and later in the Department of Rheumatology, LUMC, Leiden. I performed the first cross-disease meta-analysis between coeliac disease and rheumatoid arthritis, which involved more than 50,000 subjects (Zhernakova et al. 2011; Gutierrez et al. Hum Mol Genetics 2015). I also set up and led an international collaboration to analyse copy-number variants in the FC-gamma receptor (FcγR) locus in relation to autoimmune diseases (Franke et al. Eur J Hum Gen 2015), and worked on HLA fine-mapping and genetic factors that determine the severity of rheumatoid arthritis.
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