Polygenic risk and hazard scores for Alzheimer's disease prediction.

OBJECTIVE: Genome-wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age-specific genetic risk for AD. The aim of this study was to quantify the age-specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. METHODS: Quantification of individual differences in age-specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age-specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P-value thresholds for disease association. RESULTS: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10-12) was observed for PRS based upon genome-wide significant SNPs (P ≤ 5 × 10-8). The strength of association was weaker with less stringent SNP selection thresholds. INTERPRETATION: Both PRS and PHS can be used to predict an age-specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10-3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10-3, the age-specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study)

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Select allometric relationships of female (open circles, dashed line) and male (closed circles, solid line) <i>Hadrurus arizonensis</i>.

<p>A–F depict static allometric scaling relationships of select body characters with metasoma segment 1 width (Met 1 W) as the reference character. A. Prosoma length (Pro L) plot illustrates a difference in y-intercept between the sexes. B. Chela height (Chela H) illustrates no difference between the sexes. C. Telson width (Tel W) illustrates a difference in slopes between the sexes. D–F Illustrate differences in both y-intercept and in shifts along the slope for metasoma length (Met L), total length (Tot L), and pectine length (Pec L). Scales are logarithmic. N = 84–90 females and 65–83 males. Additional details are supplied in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120392#pone.0120392.s004" target="_blank">S3 Table</a>.</p

Morphology of representative Desert Hairy scorpion (<i>Hadrurus arizonensis</i>).

<p>Body components measured in this study are labeled.</p

Effects of reference character on allometric trends of body components.

<p>Allometric slopes (± 95% CI) determined from four alternative reference characters are paired against each of 16 y-axis characters for females (N = 84–90) and males (N = 65–83). The reference characters included A: prosoma length (Pro L); B: prosoma area (Pro A); C: total length (Tot L); and D: metasoma segment 1 width (Met 1 W). Bars identified with an asterisk (*) indicate a significant difference between the slope and null hypothesis of 1.0 by <i>F</i>-test of standard major axis regression. Significant slopes above 1.0 indicate positive allometry; significant slopes below 1.0 indicate negative allometry; and non-significant slopes indicate isometry. Additional details are supplied in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120392#pone.0120392.s003" target="_blank">S2 Table</a>.</p

The Dilemma of Choosing a Reference Character for Measuring Sexual Size Dimorphism, Sexual Body Component Dimorphism, and Character Scaling: Cryptic Dimorphism and Allometry in the Scorpion <i>Hadrurus arizonensis</i>

<div><p>Sexual differences in morphology, ranging from subtle to extravagant, occur commonly in many animal species. These differences can encompass overall body size (sexual size dimorphism, SSD) or the size and/or shape of specific body parts (sexual body component dimorphism, SBCD). Interacting forces of natural and sexual selection shape much of the expression of dimorphism we see, though non-adaptive processes may be involved. Differential scaling of individual features can result when selection favors either exaggerated (positive allometry) or reduced (negative allometry) size during growth. Studies of sexual dimorphism and character scaling rely on multivariate models that ideally use an unbiased reference character as an overall measure of body size. We explored several candidate reference characters in a cryptically dimorphic taxon, <i>Hadrurus arizonensis</i>. In this scorpion, essentially every body component among the 16 we examined could be interpreted as dimorphic, but identification of SSD and SBCD depended on which character was used as the reference (prosoma length, prosoma area, total length, principal component 1, or metasoma segment 1 width). Of these characters, discriminant function analysis suggested that metasoma segment 1 width was the most appropriate. The pattern of dimorphism in <i>H</i>. <i>arizonensis</i> mirrored that seen in other more obviously dimorphic scorpions, with static allometry trending towards isometry in most characters. Our findings are consistent with the conclusions of others that fecundity selection likely favors a larger prosoma in female scorpions, whereas sexual selection may favor other body parts being larger in males, especially the metasoma, pectines, and possibly the chela. For this scorpion and probably most other organisms, the choice of reference character profoundly affects interpretations of SSD, SBCD, and allometry. Thus, researchers need to broaden their consideration of an appropriate reference and exercise caution in interpreting findings. We highly recommend use of discriminant function analysis to identify the least-biased reference character.</p></div

Standardized canonical coefficients of morphological characters of <i>Hadrurus arizonenesis</i> from two separate discriminant function analyses (DFAs).

<p>DF1: Discriminant function for DFA that excluded the character prosoma area due to multicolinearity</p><p>DF2: Discriminant function for DFA that excluded the characters prosoma length and width to test the influence of prosoma area</p><p>Standardized canonical coefficients of morphological characters of <i>Hadrurus arizonenesis</i> from two separate discriminant function analyses (DFAs).</p

Sexual body component dimorphism (SBCD) in <i>Hadrurus arizonensis</i>, comparing the results of alternative reference characters.

<p>Analysis of covariance (ANCOVA) results are expressed as percent difference in marginal means between the sexes (y-axis) for each body component (x-axis groupings) when using different reference characters (covariates; indicated by bar pattern). Alternative reference characters included prosoma length (Pro L), prosoma area (Pro A), total length (Tot L), principal component 1 (PC1), and metasoma segment 1 width (Met 1 W). Percent difference was calculated as ((male marginal mean—female marginal mean)/((male marginal mean—female marginal mean)/2)) x 100. Thus, bars above zero indicate body components showing male-biased SBCD, and bars below zero indicate female-biased SBCD. Bars with an asterisk (*) indicate a significant difference between sexes. Missing bars (indicated by arrows) occur where a significant interaction between sex and the covariate (heterogeneous regression slopes) existed, precluding ANCOVA and obfuscating male-female differences. Note the incongruent interpretations of SBCD depending on which reference character is used in the ANCOVA. Additional details are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0120392#pone.0120392.s002" target="_blank">S1 Table</a>.</p