TY - JOUR TI - Nomograms of human hippocampal volume shifted by polygenic scores AU - Janahi, Mohammed AU - Aksman, Leon AU - Schott, Jonathan M AU - Mokrab, Younes AU - Altmann, Andre A2 - Miller, Karla L A2 - Chin, Jeannie A2 - Marquand, Andre F A2 - Bethlehem, Richard AI VL - 11 PY - 2022 DA - 2022/08/08 SP - e78232 C1 - eLife 2022;11:e78232 DO - 10.7554/eLife.78232 UR - https://doi.org/10.7554/eLife.78232 AB - Nomograms are important clinical tools applied widely in both developing and aging populations. They are generally constructed as normative models identifying cases as outliers to a distribution of healthy controls. Currently used normative models do not account for genetic heterogeneity. Hippocampal volume (HV) is a key endophenotype for many brain disorders. Here, we examine the impact of genetic adjustment on HV nomograms and the translational ability to detect dementia patients. Using imaging data from 35,686 healthy subjects aged 44–82 from the UK Biobank (UKB), we built HV nomograms using Gaussian process regression (GPR), which – compared to a previous method – extended the application age by 20 years, including dementia critical age ranges. Using HV polygenic scores (HV-PGS), we built genetically adjusted nomograms from participants stratified into the top and bottom 30% of HV-PGS. This shifted the nomograms in the expected directions by ~100 mm3 (2.3% of the average HV), which equates to 3 years of normal aging for a person aged ~65. Clinical impact of genetically adjusted nomograms was investigated by comparing 818 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database diagnosed as either cognitively normal (CN), having mild cognitive impairment (MCI) or Alzheimer’s disease (AD) patients. While no significant change in the survival analysis was found for MCI-to-AD conversion, an average of 68% relative decrease was found in intra-diagnostic-group variance, highlighting the importance of genetic adjustment in untangling phenotypic heterogeneity. KW - polygenic score KW - neuroimaging KW - genetics KW - normative modelling KW - bioinformatics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -