Background and hypothesis:

Diarrhoea, as defined by the World Health Organization (WHO), is the passage of loose stool by an individual, at least three times a day, or more frequently than normal. It usually lasts less than 7 days and it can course with or without fever and vomiting. It is most commonly caused by intestinal infection that is transmitted faecal-orally, and infants and pre-school children have higher risk of infection. Children up to age 3 have an average of one to two episodes per year, with peak incidence between the ages of 6 and 23 months.

In the first 5 years of life, approximately 70% of diarrhoea cases are caused by viruses (40% Rotaviruses and 30% others such as Noroviruses and Adenoviruses), 20% by bacteria (Campylobacter spp, Yersinia spp, Salmonella spp, Shigella spp or pathogenic Escherichia coli) and 5% by parasites (Lamblia spp, Cryptosporidia spp or Entamoeba histolytica).

Infection depends on the pathogen strain and on the host genetic background. Heritability for early childhood diarrhoea in Brazil has been estimated in 54%. Histo-blood group antigens (HBGAs) are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori, Noroviruses and Rotavirus.

We performed a preliminary GWAS on diarrhoea in INMA (N=700 children, diarrhoea yes/no during the first year of life based on questionnaire data), and among the top hits (p value ~ 10.E-06), we identified SNPs on one of the HBGA genes.

Aim:

We aim to to perform a genome-wide association (GWA) study meta-analysis on diarrhoea during first years of life.

Exposure variables:

-GWAS data imputed with 1000G project

Outcome variables:

-Diarrhea with or without doctor visit, interview or doctor diagnosis at age 1-1.5y

-Diarrhea with or without doctor visit, inerview or doctor diagnosis at age 2-2.5y

-Diarrhea with doctor visit, interview or doctor diagnosis at age 1-1.5y

-Diarrhea with doctor visit, interview or doctor diagnosis at age 2-2.4y

Confounding variables:

-Sex

Variables needed for exclusions:

-Preterm (less than 37 completed weeks of gestation)

-Congenital anomalies, where known (e.g. Down's syndrome, trisomy 18)

-Stillbirth

-One of sibling/twins or correction

-Non-European ancestry

Maybe in further steps other covariates will be needed (breastfeeding, day care attendance, siblings at birth...)