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Exome sequencing followed by genotyping suggests SYPL2 as a susceptibility gene for morbid obesity.

Jiao H, Arner P, Gerdhem P, Strawbridge RJ, Näslund E, Thorell A, Hamsten A, Kere J, Dahlman I - Eur. J. Hum. Genet. (2014)

Bottom Line: We used exome sequencing to identify variants associated with morbid obesity.Mice lacking Sypl2 has been reported to display reduced body weight.In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5' upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10(-5)) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat.

No MeSH data available.


Related in: MedlinePlus

Overview of working processes. Unpublished SNVs: variants that are not included in SNP135.
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fig1: Overview of working processes. Unpublished SNVs: variants that are not included in SNP135.

Mentions: We used the following filtering criteria to select low-frequency and rare single-nucleotide variants (SNVs) from exome sequencing data. Those SNVs enriched in morbidly obese subjects were taken forward for validation (Figure 1). First, we filtered for variants with a depth of 5 × and mapping quality (MQ) ≥20. Then we looked for putatively functional variants, that is, variants from exonic regions, splicing sites or 5′ upstream regions. In the next step, we compared the occurrences of a variant between obese and control pools. Only variants called in ≥2 obese pools, but with no call or called once in control pools, were used in the further filtering step; this step was applied to avoid potential false-positive variants. The last filtering was based on allele frequency. We looked for low-frequency and rare SNVs, that is, variants that were not found in public databases or known SNPs with a MAF≤5% in general populations (1000 Genomes project 2011 May release).


Exome sequencing followed by genotyping suggests SYPL2 as a susceptibility gene for morbid obesity.

Jiao H, Arner P, Gerdhem P, Strawbridge RJ, Näslund E, Thorell A, Hamsten A, Kere J, Dahlman I - Eur. J. Hum. Genet. (2014)

Overview of working processes. Unpublished SNVs: variants that are not included in SNP135.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538196&req=5

fig1: Overview of working processes. Unpublished SNVs: variants that are not included in SNP135.
Mentions: We used the following filtering criteria to select low-frequency and rare single-nucleotide variants (SNVs) from exome sequencing data. Those SNVs enriched in morbidly obese subjects were taken forward for validation (Figure 1). First, we filtered for variants with a depth of 5 × and mapping quality (MQ) ≥20. Then we looked for putatively functional variants, that is, variants from exonic regions, splicing sites or 5′ upstream regions. In the next step, we compared the occurrences of a variant between obese and control pools. Only variants called in ≥2 obese pools, but with no call or called once in control pools, were used in the further filtering step; this step was applied to avoid potential false-positive variants. The last filtering was based on allele frequency. We looked for low-frequency and rare SNVs, that is, variants that were not found in public databases or known SNPs with a MAF≤5% in general populations (1000 Genomes project 2011 May release).

Bottom Line: We used exome sequencing to identify variants associated with morbid obesity.Mice lacking Sypl2 has been reported to display reduced body weight.In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5' upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10(-5)) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat.

No MeSH data available.


Related in: MedlinePlus