Grouper is an economically important fish in China. However, it exhibits a high frequency of skeletal abnormalities, particularly vertebral deformities. The molecular mechanisms underlying fish vertebral deformities are still poorly understood. In this study, a HiSeq™ 4000 platform (Illumina) was used to analyze the transcriptomic profiles of the brain, pituitary, and vertebrae from normal fish (NF) and fish with lordosis (LF) of Yunlong grouper. A total of 87,888 unigenes were assembled with lengths that varied from 201 to 28,922 bp and a N50 length of 2670 bp. A total of 36,268 unigenes were functionally annotated by BLAST alignments. A total of 2875 significantly differentially expressed genes (DEGs) were identified between the NF group and the LF group, including 706 upregulated unigenes and 2169 downregulated unigenes in LF. GO and KEGG pathway enrichment analyses showed that DNA binding, transmembrane receptor activity, cytokine receptor interaction, neuroactive ligand-receptor interaction, calcium signaling pathway and ECM-receptor interaction HIF-1 signaling pathway, and mineral absorption may be involved in the formation of vertebral deformities. Furthermore, weighted gene co-expression network analyses, including three modules (turquoise, yellow, and blue), significantly positively corrected with vertebral deformities. A network map that included these three modules enabled the identification of a series of hub genes, including claudin-22-like (cldn22), fibronectin type III domain-containing protein 1 isoform X2 (fndc1l2), E3 ubiquitin-protein ligase NRDP1-like (rnf41), and Catenin alpha-2 (ctnna1). We found that the levels of most genes in the blue module were closely related to the expression of parvalbumin, thymic CPV3-like isoform X2 (ocm), platelet glycoprotein Ib alpha chain (gp1ba), and matrix metalloproteinase-9 (mmp9), suggesting that this module is associated with skeletal development. Some uncharacterized genes associated with known bone-related genes, including Unigene0067643, Unigene0056862, and Unigene0059867, were detected by a weighted gene co-expression network analysis. A detailed functional investigation of these networks and genes will further improve our understanding of the molecular mechanisms that underlie the formation of lordosis in fish.