Polygenic risk score may improve screening for short stature risk in adulthood
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A polygenic risk score can predict adult short stature among children with accuracy similar to the use of midparental height, according to data published in The Journal of Clinical Endocrinology & Metabolism.
“Clinicians could consider using a polygenic risk score when trying to decide whether to use therapies to prevent short stature, particularly when bone age is not available and the height of one parent is known,” Brent Richards, MD, MSc, professor of medicine in the department of human genetics at McGill University in Montreal, told Healio. “It is particularly helpful for children who do not know the height of both parents.”
Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared with midparental height, Richards and colleagues wrote in the study background.
“Various approaches have been developed and clinically adopted for adult height prediction, based on current height measures and bone age as measured by hand and wrist X-ray, such as the Bayley-Pinneau method, the Tanner-Whitehouse methods and the Roche-Wainer-Thissen method,” the researchers wrote. “While bone age has been recognized as one of the most important predictors of final adult height and has been employed in these prediction approaches, measuring bone age requires an X-ray, a radiologist’s interpretation of the images, and calculation of the predicted adult height.”
The researchers developed a polygenic risk score for adult height, based on a meta-analysis of genome-wide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.
The cohort included 442,599 genotyped white British individuals participating in the UK Biobank and 941 genotyped child-parent trios of European ancestry from the ALSPAC cohort. Standing height was measured using stadiometer; standing height 2 standard deviations below the sex-specific population average was considered short stature.
Researchers found that, combined 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 short stature in adulthood with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of midparental height.
“Using an external cohort of 941 samples, we demonstrated that, for the first time, a polygenic risk score was able to perform as well as the midparental height in predicting children’s adult height and in identifying children who would have adult short stature,” the researchers wrote. “Further, combining midparental height and the polygenic risk score provided better prediction accuracy than either metric alone. The polygenic risk score could also substitute midparental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.”
The researchers noted that a polygenic risk score could be considered as an alternative or adjunct to midparental height to improve screening for children at risk for developing short stature as adults, although they wrote that the data were restricted to those of European ancestry.
Richards noted that polygenic risk scores will improve with increased sample sizes.
For more information:
Brent Richards, MD, can be reached at brent.richards@mcgill.ca; Twitter: @BrentRichards19.
Perspective
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The study by Lu and colleagues demonstrates the strong correlation of a polygenic risk score and adult height and validates its use in a relevant cohort. Using this relatively inexpensive technology, the lifetime risk for adult short stature can be estimated in a child at any age. The addition of parental height data increased the predictive power of the polygenic risk score analysis.
The polygenic risk score holds promise as a potential replacement for prediction of height using bone age X-ray analysis without requiring radiation or image analysis expertise. It will be important to validate this methodology in broader genetic backgrounds, other longitudinal cohorts and clinics caring for children with growth disorders.
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