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Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging
被引:77
|作者:
Hou, Ying-Chen Claire
[1
]
Yu, Hung-Chun
[1
]
Martin, Rick
[1
]
Cirulli, Elizabeth T.
[1
]
Schenker-Ahmed, Natalie M.
[1
,2
]
Hicks, Michael
[1
]
Cohen, Isaac V.
[1
,3
]
Jonsson, Thomas J.
[4
]
Heister, Robyn
[1
]
Napier, Lori
[1
]
Swisher, Christine Leon
[1
]
Dominguez, Saints
[1
]
Tang, Haibao
[1
]
Li, Weizhong
[5
]
Perkins, Bradley A.
[1
]
Barea, Jaime
[1
]
Rybak, Christina
[1
]
Smith, Emily
[1
]
Duchicela, Keegan
[1
]
Doney, Michael
[1
]
Brar, Pamila
[1
,5
]
Hernandez, Nathaniel
[1
]
Kirkness, Ewen F.
[5
]
Kahn, Andrew M.
[1
,6
]
Venter, J. Craig
[1
,5
]
Karow, David S.
[1
,2
]
Caskey, C. Thomas
[1
,7
]
机构:
[1] Human Longev Inc, San Diego, CA 92121 USA
[2] Univ Calif San Diego, Sch Med, Dept Radiol, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA
[4] Metabolon Inc, Morrisville, NC 27713 USA
[5] J Craig Venter Inst, La Jolla, CA 92037 USA
[6] Univ Calif San Diego, Sch Med, Div Cardiovasc Med, La Jolla, CA 92037 USA
[7] Baylor Coll Med, Mol & Human Genet, Houston, TX 77030 USA
来源:
关键词:
genomics;
advanced imaging;
precision medicine;
deep phenotyping;
metabolomics;
CARDIOVASCULAR RISK;
AMERICAN-COLLEGE;
ADULT PATIENTS;
RARE VARIANTS;
ASSOCIATION;
RESOURCE;
NETWORK;
HEALTH;
GENE;
D O I:
10.1073/pnas.1909378117
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencingwith deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (> 75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.
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页码:3053 / 3062
页数:10
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