Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Abstract

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10^-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R² = 0.15; P < 2.0 × 10^-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Keywords: GWAS; Kleine-Levin syndrome; bipolar disorder; birth difficulties; hypersomnia.

Fig. 1.

Multiethnic GWAS in 673 KLS cases and 15,431 control individuals. (A) Manhattan plot of the metaanalysis association (discovery cohort) results from SNP-based GWAS study. The x axis shows genomic location by chromosome, and the y axis shows −log10 P values. Red horizontal line indicates genome-wide significant P value threshold of 5 × 10⁻⁸. Individual loci are annotated. (B) Manhattan plot of gene-based association test association results. SNPs were mapped to 18,247 protein coding genes (distance 0). Genome-wide significance (red dashed line) was defined at P = 0.05/18,247 = 2.74 × 10⁻⁶.

Fig. 2.

Regional association plot of the GWA significance of chromosome 3 flanked by rs76652637 and rs11706780 in the 3′ region of TRANK1. Highest significance was observed at rs71947865 (OR = 1.47, P = 8.6 × 10⁻⁹, presence of G versus GGGAGCCA). The variants are color coded by the magnitude of LD with the rs71947865.

Fig. 3.

(A) The TRANK1-region SNP associations in KLS cases stratified by birth years; the y axis represents the odds ratio of the effect allele, while the x axis is the birth year. P value of the association is labeled. (B) The TRANK1-region SNP associations in KLS cases stratified by birth difficulties; the y axis represents the odds ratio of the effect allele, while the x axis is the presence of birth difficulties.

Fig. 4.

Phenotypic variance explained by PRSs (pseudo R²) built on the KLS discovery cohort and tested on the KLS replication cohort; the y axis is the pseudo R², while the x axis represents the P value thresholds. The color gradient over each bar is representative of the P value association between the PRS and the KLS trait in replication cohort.