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An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.

ABSTRACT: More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.

SUBMITTER: Jin B

PROVIDER: S-EPMC8997344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The very rare Mexican Picea chihuahuana tree community covers an area of no more than 300 ha in the Sierra Madre Occidental. This special tree community has been the subject of several studies aimed at learning more about the genetic structure and ecology of the species and the potential effects of climate change. The spatial distribution of trees is a result of many ecological processes and can affect the degree of competition between neighbouring trees, tree density, variability in size and distribution, regeneration, survival, growth, mortality, crown formation and the biological diversity within forest communities. Numerous scale-dependent measures have been established in order to describe spatial forest structure. The overall aim of most of these studies has been to obtain data to help design preservation and conservation strategies. In this study, we examined the spatial distribution pattern of trees in the P. chihuahuana tree community in 12 localities, in relation to i) tree stand density, ii) diameter distribution (vertical structure), iii) tree species diversity, iv) geographical latitude and v) tree dominance at a fine scale (in 0.25 ha plots), with the aim of obtaining a better understanding of the complex ecosystem processes and biological diversity. Because of the strongly mixed nature of this tree community, which often produces low population densities of each tree species and random tree fall gaps caused by tree death, we expect aggregated patterns in individual Picea chihuahuana trees and in the P. chihuahuana tree community, repulsive Picea patterns to other tree species and repulsive patterns of young to adult trees. Each location was represented by one plot of 50 x 50 m (0.25 ha) established in the centre of the tree community. The findings demonstrate that the hypothesis of aggregated tree pattern is not applicable to the mean pattern measured by Clark-Evans index, Uniform Angle index and Mean Directional index of the uneven-aged P. chihuahuana trees and P. chihuahuana tree community and but to specific spatial scales measured by the univariate L-function. The spatial distribution pattern of P. chihuahuana trees was found to be independent of patches of other tree species measured by the bivariate L-function. The spatial distribution was not significantly related to tree density, diameter distribution or tree species diversity. The index of Clark and Evans decreased significantly from the southern to northern plots containing all tree species. Self-thinning due to intra and inter-specific competition-induced mortality is probably the main cause of the decrease in aggregation intensity during the course of population development in this tree community. We recommend the use of larger sampling plots (> 0.25 ha) in uneven-aged and species-rich forest ecosystems to detect less obvious, but important, relationships between spatial tree pattern and functioning and diversity in these forests.

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An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.

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