Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis

Abstract

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference >10°) and 2 concordant (Cobb angle difference ≤2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Epigenetic and Genetic Factors Related to Curve Progression in Adolescent Idiopathic Scoliosis: A Systematic Scoping Review of the Current Literature

“…According to the research performed, a total of 40 papers [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ] met the inclusion criteria and were considered for review. Of these studies, twenty-one [ 18 , 19 , 21 , 24 , 31 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 , 45 ,…”

“…According to the Oxford level of evidence scale, ten [ 16 , 17 , 27 , 28 , 29 , 32 , 46 , 48 , 49 , 53 ] of the included studies had a level of evidence IV, twenty-six [ 18 , 19 , 20 , 21 , 23 , 24 , 26 , 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 44 , 45 , 47 , 50 , 51 , 52 , 54 , 55 ] studies had a level of evidence III, while the remaining studies had a level of evidence II [ 22 , 25 , 30 , 43 ].…”

“…The median age at the first visit ranged from 12.2 ± 1.2 to 18.5 ± 1.8 years and the median follow-up ranged from 12 months to 42 months. Asiatic populations (Chinese, Japanese, and Korean) [ 9 , 16 , 17 , 20 , 21 , 23 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 47 , 51 , 53 , 54 , 55 , 56 ] were the most studied by authors, but Caucasian populations (Europeans, Polish, and French-Canadian) [ 24 , 25 , 26 , 27 , 41 , 43 , 46 , 48 , 49 , 52 ], Russian [ 19 ], and Turkish [ 18 ] populations were also evaluated for possible associations. Two studies did not accurately describe the population demographics [ 30 , 43 ].…”

“…In other studies [ 23 , 33 , 34 , 37 , 38 , 41 , 49 , 54 , 55 ], the diagnosis was generic or without accurate subtype distribution (i.e., thoracic, or thoracolumbar curve) or not reported [ 18 , 20 , 21 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 35 , 36 , 43 , 44 , 45 , 46 , 48 , 52 , 56 ].…”

“…As for the initial Cobb Angle, it was accurately described in twenty-three studies [ 16 , 17 , 18 , 19 , 21 , 26 , 27 , 29 , 31 , 32 , 34 , 35 , 37 , 39 , 40 , 41 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 55 ] with a median angle at first visit ranging from 20.1° ± 8.3° to 77.4° ± 16.1°; other studies reported the range of values or the minimum/maximum values [ 20 , 22 , 23 , 25 , 28 , 33 , 36 , 38 , 42 , 51 , 52 , 53 , 54 ].…”