Prof. Alexandra (Sasha) Zhernakova, MD, PhD

PhD thesis: The autoimmune puzzle – shared and specific genetics of immune-related diseases. 2009, Graduated cum laude, Utrecht University, the Netherlands

See Google Scholar or PubMed for my papers

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News

• March 2024 - Awarded NWO Vici grant to study the development and causes of allergies in the first years of life. For more information see the UMCG press release.
• March 2023 - Inaugural lecture "The Gut Microbiome: A universe inside us" in honor of her appointment as Professor of Human Genome and Exposome. pdf of lecture
• November 2022 - Awarded the G.A. Gamow award by the Russian-American Association of Scientists "for the elucidation of the role the intestinal microbiome and viriome play in aging and disease development." For more information see the press release.
• July 2020 - Appointed Full Professor of the human genome and exposome.
• September 2019 - Awarded NWO Gravitation grant ExposomeNL, focused on investigation of the role of exposome, in particular the gut microbiome, in relation to host factors and human diseases.
• May 2017 - Awarded VIDI grant for the project: The breast milk microbiome: the missing link between mothers and their babies’ health. See news item here.
• April 2017 - Appointed Associate professor in genetic and environmental factors in the development of autoimmune and gastrointestinal diseases and ageing.
• September 2016 - Awarded ERC starting grant for the project: BabyVir: The role of the virome in shaping the gut ecosystem during the first year of life.
• September 2016 - IBS large-scale genetic project launched - The Bellygenes initiative. This initiative "coordinated by researchers at Karolinska Institutet and the UMCG, will study the genetic makeup of 800,000 Europeans in relation to irritable bowel syndrome and associated symptoms."

• April 2014 - Obtained the BBMRI grant for measuring the telomere length in a populational cohort of 1,500 individuals.

My research team studies the role of various genetic and environmental factors in the predisposition to common diseases and traits, including gastrointestinal and autoimmune diseases and ageing. A major research line focuses on the composition of the gut microbiome and virome in cohorts of adults and babies. We explore 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.

Current work

In May 2017, I was awarded an NWO-VIDI grant to study the breast milk microbiome in a new cohort called LifeLines-NEXT. 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. Since 2012 I have held a Rosalind Franklin Fellowship from the University of Groningen.

Ongoing research lines in my group:

1. Host and environmental factors that shape the human microbiome and their role in 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. We are also exploring the microbiome of breast milk and its relation with gut microbiome and health factors.

Other work has included sequencing and analysing the gut microbiome in a unique, well-phenotyped cohort of 10,000 individuals – currently the largest such cohort available. We found a strong link of microbiota with several human phenotypes, including a strong link between the microbiome and lipid metabolism (Fu et al. Circulation Research 2015; awarded the Best Paper prize by Circulation Research in 2015), stool consistency (Tigchelaar et al. Gut 2015), medication (Imhann et al. Gut 2015; Vich Vila et al. Nat. Communications 2020), diet (Bonder et al. Genome Medicine 2016), diseases (Vich Vila STM 2018) and over 100 other intrinsic and environmental factors (Zhernakova et al. Science 2016; Falony et al. Science 2016; news). An extensive analysis of >200 exposome factors in relation to the gut microbiome and host health is currently ongoing in a cohort of ~9000 Lifelines participants. I am also leading the MiBioGen consortium, which explores the role of host genetics in the gut microbiome in a large multi-center meta-analysis (Kurilshikov et al, submitted).

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.

3. Fine-mapping the HLA locus in relation to immune diseases and aging

HLA is an extensive 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.

Group members

Postdocs: Alexander Kurilshikov, Anastasia Gulyaeva, Ayse Demirkan
PhD students: Trishla Sinha, Sanzhima Garmaeva, Johanne Spreckels, Siobhan Brushett. Co-supervision of Lianmin Chen, Marwah Doestzada, Daoming Wang, Sergio Andreu Sanchez, Ailine Lopez
Technician: Marloes Kruk

Past members
Postdocs: Maria Carmen Cenit
PhD students: Arnau Vich Vila (PhD thesis, awarded cum laude, 2019, “Understanding the gut ecosystem: bugs, drugs and diseases”), Marc Jan Bonder (PhD thesis, awarded cum laude, 2017, "The interplay between genetics, the microbiome, DNA‐methylation & gene‐expression"), Ettje Tigchelaar (PhD thesis, 2016, "From bugs to buttermilk: Epidemiological and molecular aspects of gut health"), 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
BSC/MSc student internships: Trishla Sinha, Anastassia Blanter, Kees Neerdeveer, Debbie van Dussen, Janneke Pietersma, Milla Brandao Gois, Wouter Stegeman, Beheshta Doesdada

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.

In 2012, I became a Rosalind Franklin Fellow in the UMCG and started my own research lines in ageing, microbiome, virome and exposome.