Body shape is a complex and plastic trait with a high impact on fish performance and commercialization. Shape is particularly relevant in flatfish with highly asymmetric bodies. In this study we investigated the skeleton features, transcriptomic profiles and genomic regions in two Senegalese sole groups from a full-sib family with positive (named as HE) or negative (LE) breeding values for body ellipticity (ELL). Soles from HE group were heavier and displayed more elongated bodies than LE. A skeleton analysis showed that HE had a higher number of vertebrae, longer vertebral bodies and intervertebral spaces and a lower incidence of skeletal fusions than LE. With respect to the gender effect, females showed a higher height of ventral body and some differences in the ratio urostyle to skeleton length than males for similar ELL values. The PCA analysis using 28 dimensionless morphological traits indicated that PC1 and PC2 explained 51.3% of the total variance and they were mainly associated with ELL and gender variation, respectively. Expression analysis using two factors (ELL and gender) revealed a major effect of gender in muscle, pterygiophores and liver with 6764, 6506 and 7559 differentially expressed transcripts (DETs) between sexes, respectively. In brain, only 16 DETs were identified. When HE and LE were compared controlling by gender, we identified the subset of DETs with conserved responses in both sexes or those regulated in a sex-specific manner in each tissue. A comparison across tissues identified 31 ubiquitous transcripts as differentially expressed in at least two of them. Functional analysis showed that liver and pterygiophores had the highest number of enriched gene ontology categories (24 and 14, respectively). Some of these enriched pathways were related to regulation of cell cycle, cell structure and shape, locomotory behavior, immune system, hormonal responses and homeostasis. A BSR-Seq analysis confirmed five significant genomic windows associated with ELL by using the tricube-smoothed G' and Fst statistics. Windows located in linkage groups (LG) 5 and LG14 included the malt1 and vtg3 genes, respectively, that were also detected within the subset of ubiquitous DETs. Moreover, malt1 appeared located very close to the bmpr1b gene within the significance hotspot of LG5 indicating that mediators of the inflammatory responses and BMP signaling pathway could be responsible for the differences found in the skeleton features and body ellipticity.