Abstract
ContextAdult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.ObjectiveTo develop a polygenic risk score for adult height and evaluate its clinical utility.DesignA polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.SubjectsParticipants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.InterventionsNone.Main Outcome MeasuresStanding height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature.ResultsCombined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child’s parent’s height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.ConclusionsA polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
Highlights
Predicting adult height is important to monitoring childhood growth and development, for children in some jurisdictions who may be considered for growth hormone therapy for “idiopathic short stature” [1,2,3]
We evaluated how well such a polygenic risk score performed compared to mid-parental height in its ability to predict adult height of 941 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) [22,23]
CI: 67.9%-74.1%) of the total variance in adult height (Fig. 2A). This value was similar to the 72.6% (69.6%-75.6%) variance explained by mid-parental height (Fig. 2B) and was consistent in 541 females [adjusted R2 = 38.5% for the polygenic risk score vs 41.8% for mid-parental height] and 400 males [adjusted R2 = 37.9% for the polygenic risk score vs 45.0% by mid-parental height]
Summary
Predicting adult height is important to monitoring childhood growth and development, for children in some jurisdictions who may be considered for growth hormone therapy for “idiopathic short stature” [1,2,3]. In the 19th century, the concept of mid-parental height was proposed [12] It has been either used directly as an empirical predictor of adult height or incorporated into other height prediction methods, such as the bone age-free Khamis-Roche method [13], to represent the genetic contribution to an individual’s adult height. We sought to develop and optimize a polygenic risk score for adult height using state-of-the-art methods based on 607 346 individuals of European ancestry from the UK Biobank and the Genetic Investigation of Anthropometric Traits (GIANT) study [21]. We evaluated how well such a polygenic risk score performed compared to mid-parental height in its ability to predict adult height of 941 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) [22,23]. We tested the ability of the polygenic risk score to identify children who would later have an adulthood short stature
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