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
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.
引用
收藏
页码:3053 / 3062
页数:10
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