Zhernakova Group – Complex diseases and traits

Dr Alexandra (Sasha) Zhernakova’s group has three research lines (see below) and is starting a study into the microbiome of breast milk, ”The breast milk microbiome: the missing link between mothers and their babies’ health”, to be funded by her 2017 VIDI grant:

1. Her main research is on: Investigating host and environmental factors that shape the human microbiome and understanding the role of the microbiome in relation to human diseases and aging

We have recently sequenced and analysed the gut microbiome in a unique, well-phenotyped cohort of 1,500 individuals (LifeLines Deep, see Tigchelaar et al. BMJ open 2015) – this is currently the largest such cohort available. We were able to discover a strong link of microbiota with several human phenotypes. We have shown the link of 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;8(1):45. doi: 10.1186/s13073-016-0295-y.

The effect of host genetics on the gut microbiome. Bonder MJ,  et al. Nat Genet. 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;6:8570. doi: 10.1038/ncomms9570.

Shah S, Bonder MJ, … Zhernakova A, … Franke L, Deary IJ, Visscher PM. Improving phenotypic prediction by combining genetic and epigenetic associationsAm J Hum Genet. 2015;97:75-85. doi: 10.1016/j.ajhg.2015.05.014

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, 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. pii: ddv455.

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

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;47(6):577-8.

Group members

Postdoc: Alexander Kurilshikov
PhD students:  Soesma Medema-Jankipersadsing
Technician: Jody Arends

Past members
Postdocs: Jingyuan Fu, Maria Carmen Cenit
PhD students: Marc Jan Bonder, PhD thesis on The interplay between genetics, the microbiome, DNA-methylation & gene‐expression (2017); Ettje Tigchelaar-Feenstra, PhD thesis, From bugs to buttermilk: epidemiological and molecular aspects of gut health 2016; 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

The 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. They 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. Sasha Zhernakova holds an ERC starting grant and a Rosalind Franklin Fellowship from the University of Groningen.