title: Quantifying the extent to which index event biases influence large genetic association studies.
abstract: As genetic association studies increase in size to 100 000s of individuals, subtle biases may influence conclusions. One possible bias is 'index event bias' (IEB) that appears due to the stratification by, or enrichment for, disease status when testing associations between genetic variants and a disease-associated trait. We aimed to test the extent to which IEB influences some known trait associations in a range of study designs and provide a statistical framework for assessing future associations. Analyzing data from 113 203 non-diabetic UK Biobank participants, we observed three (near TCF7L2, CDKN2AB and CDKAL1) overestimated (body mass index (BMI) decreasing) and one (near MTNR1B) underestimated (BMI increasing) associations among 11 type 2 diabetes risk alleles (at P  <  0.05). IEB became even stronger when we tested a type 2 diabetes genetic risk score composed of these 11 variants (-0.010 standard deviations BMI per allele, P  =  5 × 10- 4), which was confirmed in four additional independent studies. Similar results emerged when examining the effect of blood pressure increasing alleles on BMI in normotensive UK Biobank samples. Furthermore, we demonstrated that, under realistic scenarios, common disease alleles would become associated at P <  5 × 10- 8 with disease-related traits through IEB alone, if disease prevalence in the sample differs appreciably from the background population prevalence. For example, some hypertension and type 2 diabetes alleles will be associated with BMI in sample sizes of  >500 000 if the prevalence of those diseases differs by >10% from the background population. In conclusion, IEB may result in false positive or negative genetic associations in very large studies stratified or strongly enriched for/against disease cases.
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bancks
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Sam E
authors.initials: SE
authors.lastname: Jones
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne 1010, Switzerland.|Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Aaron
authors.initials: A
authors.lastname: McDaid
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Beaumont
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Donnelly
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
authors.forename: Archie
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tyrrell
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Tuke
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ruth
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.affiliation: Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.affiliation: Generation Scotland, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Division of Cardiovascular & Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Palmer
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne 1010, Switzerland.|Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
mesh_terms: D000483:Alleles; D001786:Blood Glucose / Q000235:genetics; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D001786:Blood Glucose