Maria Pettersson1,2, Heli Viljakainen3, Petra Loid3, Taina Mustila4, Minna Pekkinen5, Miriam Armenio1,2, Johanna C Andersson-Assarsson6, Outi Mäkitie1,2,3,5, Anna Lindstrand1,2,7. 1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 77, Sweden. 2. Center for Molecular Medicine, Karolinska Institutet, Stockholm 171 77, Sweden. 3. Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki FI-00029, Finland. 4. Department of Pediatrics, Seinäjoki Central Hospital, Seinäjoki FI-60100, Finland. 5. Folkhälsan Institute of Genetics, Helsinki FI-00290, Finland. 6. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 90, Sweden. 7. Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 77, Sweden.
Abstract
Context: Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
Context: Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
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Authors: Petra Loid; Taina Mustila; Riikka E Mäkitie; Heli Viljakainen; Anders Kämpe; Päivi Tossavainen; Marita Lipsanen-Nyman; Minna Pekkinen; Outi Mäkitie Journal: Front Endocrinol (Lausanne) Date: 2020-02-21 Impact factor: 5.555