Generalization of Cortical MOSTest Genome-Wide Associations Within and Across Samples

Abstract

Genome-Wide Association studies have typically been limited to single phenotypes, given that high dimensional phenotypes incur a large multiple comparisons burden: ~1 million tests across the genome times the number of phenotypes. Recent work demonstrates that a Multivariate Omnibus Statistic Test (MOSTest) is well powered to discover genomic effects distributed across multiple phenotypes. Applied to cortical brain MRI morphology measures, MOSTest has resulted in a drastic improvement in power to discover loci when compared to established approaches (min-P). One question that arises is how well these discovered loci replicate in independent data. Here we perform 10 times cross validation within 35,644 individuals from UK Biobank for imaging measures of cortical area, thickness and sulcal depth (>1,000 dimensionality for each). By deploying a replication method that aggregates discovered effects distributed across multiple phenotypes, termed PolyVertex Score (PVS), we demonstrate a higher replication yield and comparable replication rate of discovered loci for MOSTest (# replicated loci: 348-845, replication rate: 94-95%) in independent data when compared with the established min-P approach (# replicated loci: 31-68, replication rate: 65-80%). An out-of-sample replication of discovered loci was conducted with a sample of 8,336 individuals from the Adolescent Brain Cognitive Development® (ABCD) study, who are on average 50 years younger than UK Biobank individuals. We observe a higher replication yield and comparable replication rate of MOSTest compared to min-P. This finding underscores the importance of using well-powered multivariate techniques for both discovery and replication of high dimensional phenotypes in Genome-Wide Association studies.

The genetic architecture of human cortical folding

“…Furthermore, the current findings indicate the presence of widespread genetic effects, illustrating this important characteristic of its genetic architecture; numerous variants are involved, each with a complex pattern of effects spread across the cortex. As shown by our estimates of generalization, these multivariate genetic effects on sulcal depth seem to be rather independent of ethnicity and age (40), emphasizing the fundamental neurobiological relevance for brain morphology.…”

Hemochromatosis Neural Archetype Reveals Iron Disruption in Motor Circuits

“…The C282Y homozygote classifier was used fit using a PolyVoxel Score (PVS) framework 4 as follows. Let X train represent the pre-residualized imaging matrix with N rows of individuals and M columns of voxels in the training sample.…”

Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders

“…Multivariate discoveries require a special replication procedure to ensure that a locus in question is not only showing an association in an independent sample, but also that the multivariate pattern of that association is consistent between the discovery and the replication samples. Such procedure has been established in Loughnan et al 75 For a given SNP in the discovery set, the procedure provides a composite score (one value for each individual in the validation set) obtained as a weighted sum of individuals' phenotypes, with weights derived from mass-univariate z-statistics from the discovery set. If a SNP association represents a real signal in the discovery set, we expect its composite score to be associated with the genotype in the replication sample at a nominal one-sided P<0.05, and to have a consistent effect direction.…”