A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait-A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis

Abstract

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development.

Keywords: complex trait; genetic linkage study; genetic predisposition; genome wide association study; idiopathic scoliosis; model animal.

Figure 1

In 2007, Dr. Cotrel and team listed 10 potential categories of underlying causes of scoliosis. It was a key mission of the Cotrel Foundation to find out the primary etiology of adolescent idiopathic scoliosis (AIS). They include genetics, biomechanics, neurology, Oto-Rhino-laryngology, molecular biology, endocrinology, neurophysiology, biochemistry, sensory physiology, and anatomical pathology (courtesy of the Cotrel Foundation).

Figure 2

A group photo of international research colleagues and Dr. Cotrel (right on the first row) taken during 2007 Cotrel Foundation Annual Scientific meeting (courtesy of the Cotrel Foundation).

Figure 3

Timeline of genetic research milestones of AIS showing the essential role played by Cotrel Foundation in cultivating complex trait model of AIS.

Figure 4

Genetic predisposition for AIS under perspective of a complex trait model. Plausible genes contributing to scoliosis are also shown of which many were identified by GWAS.

Figure 5

Updated 2-phase concept of AIS. With more genetic studies, more information could be filled in compared to that of first version we proposed more than a decade ago. Genes like LBX1 and BNC2 are AIS predisposition genes that contribute to initiation phase. On the other hand, environmental (Env.) factors may outweigh genetics in determining how far curve would advance.

Figure 6

An example GWAS results in AIS showing putative predisposition SNPs and their statistical significance in a Manhattan plot from Chinese AIS GWAS study [42].

Figure 7

Spine X-rays of a male patient who was first diagnosed at 12.5 years old with a 21-degree curve. Environmental and lifestyle modifications were implemented like upper limb exercise, posture awareness, and change of seating furniture. His curve reverted to 10 degrees at the age of 15 years old and the follow-up x-ray was taken after he had passed through his peak growth spurt. Bracing was not prescribed in this case. This case demonstrates that soft tissue remodeling is feasible in some selected patients.