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- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 2. |
- Yaghootkar, Hanieh, et al.
(författare)
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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:12, s. 2806-2818
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Tidskriftsartikel (refereegranskat)abstract
- Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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| 3. |
- Laird, Neil F., et al.
(författare)
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Climatology of cold season lake-effect cloud bands for the North American Great Lakes
- 2017
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Ingår i: International Journal of Climatology. - : Wiley. - 0899-8418 .- 1097-0088. ; 37:4, s. 2111-2121
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Tidskriftsartikel (refereegranskat)abstract
- Geostationary Operational Environmental Satellite (GOES) visible imagery was used to identify lake-effect (LE) clouds in the North American Great Lakes region for the cold seasons (October-March) of 1997/1998 through 2013/2014 to provide a comprehensive climatological description of the seasonal and interannual variability of LE cloud bands. During the average cold season, at least 60% of days each month had LE clouds over some portion of the Great Lakes region and nearly 75% of all LE days had LE clouds present over several lakes simultaneously. Wind-parallel bands (WPB) are observed far more frequently than any other type of LE over Lakes Superior, Michigan, and Huron during the months of December, January, and February. Over Lake Erie, the occurrence of days per month with WPB was found to be approximately 5-10% greater than days with shore-parallel bands (SPBs) throughout the entire cold season. The greatest frequency of SPB occurrences in the Great Lakes region was over Lake Ontario during the months of January and February (approximate to 20% of days). In addition, Lake Ontario was the only lake where the frequencies of WPB and SPB occurrences were fairly similar each month. The annual frequency of WPB occurrences are the most variable among the Great Lakes, decreasing in frequency from the western lakes toward the eastern lakes. Lake Ontario has the largest annual frequency of SPB occurrences and the greatest variation in SPB annual frequency. Lake Huron has the second largest annual frequency of SPB days with small interannual variation. The primary differences of the annual frequency of lake-to-lake (L2L) LE occurrences when compared with previous research were a greater variability in the L2L annual frequency of Superior-to-Michigan connections, greater frequency of Michigan-to-Huron connections, and less frequent occurrences for Superior-to-Huron and Michigan-to-Erie connections.
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