Laboratory of metabolic disease and ageing genomics
The obesity crisis is a major healthcare concern in both developed and developing nations worldwide. Obesity is not only a problem in childhood and adulthood but it also tracks into older ages. At the same time, we are in the midst of an ageing population crisis with many nations, including Singapore, facing massive healthcare burdens due to prolonged lifespan spent in poor health. How inherent genetic risks contribute to accelerate ageing processes, especially in Asian populations is not well understood.
My research is focused towards using a breath of genomic data to understand biological processes of accelerated ageing and how these may impact upon health outcomes later in life. The group routinely performs large-scale genetic association studies through genome-wide association studies (GWAS) and more detailed sequencing studies for metabolic traits such as obesity levels and ageing related biomarkers such as telomere length attrition. These have enabled identification of numerous germline genetic risk variants for various metabolic and ageing related traits. Our genetic studies for telomere length attrition has also highlighted potential ethnic-specific genetic associations that may be uniquely relevant to the Asian population. Leveraging on longitudinal datasets such as the Singapore Chinese Health Study with over 25 years of prospectively collected phenotypes, we follow up identified genetic findings with powerful statistical tools to ascertain potentially functional roles for specific metabolic and ageing biomarkers with risks of incident diseases (common cancers, cardiovascular diseases, type 2 diabetes mellitus), major mortalities and overall longevity and healthy ageing status.
Understanding precise biological dysfunctions that contribute to disease and ageing outcomes requires additional detailed investigations at the disease relevant tissues and cells. The group extends genetic findings through detailed omics interrogations in primary tissues and cell-types from appropriate patient samples. These include determination of ageing biomarkers together with genome-wide transcriptomic evaluations of sputum immune cell-types to understand a potential role for telomere length attrition in immune competence, which we had reported to be especially relevant to increased respiratory disease and mortality risks. Other primary studies involve detailed RNA-sequencing evaluations of various adipose tissues from bariatric weight-loss surgery patients and kidney transcriptomic studies in renal decline patients. The group actively seeks to integrate germline genetic information, multiple layers of detailed omics data with improved ageing molecular phenotypes to provide added insights to metabolic dysfunctions in relation to ageing processes and outcomes.
- Chang X, Zhou Y-F, Wang L, Liu J, Yuan J-M, Khor C-C, Heng C-K, Pan A, Koh W-P#, Dorajoo R#. Genetic associations with healthy ageing among Chinese adults. npj Aging. 2022 (Accepted-in-principle).
- Lim HF#, Tan NS, Dehghan R, Shen M, Liew MF, Bee SWL, Sia YY, Liu J, Khor C-C, Kwok I, Ng LG, Angeli V, Dorajoo R#. Shortened telomere length in sputum cells of bronchiectasis patients is associated with dysfunctional inflammatory pathways. Lung. 2022 (Accepted-in-principle).
- Chang X, Gurung RL, Wang L, Jin A, Li Z, Wang R, Beckman KB, Adams-Haduch J, Meah WY, Sim KS, Lim WK, Davila S, Tan P, Teo JX, Yeo KK, M Y, Liu S, Lim SC, Liu J, van Dam RM, Friedlander Y, Koh WP, Yuan JM, Khor CC, Heng CK#, Dorajoo R#. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population. Commun Biol. 2021 May 3;4(1):519. doi: 10.1038/s42003-021-02056-7. PMID: 33941849; PMCID: PMC8093266.
- Chang X, Chua KY, Wang L, Liu J, Yuan JM, Khor CC, Heng CK, Koh WP, Dorajoo R. Midlife Leukocyte Telomere Length as an Indicator for Handgrip Strength in Late Life. J Gerontol A Biol Sci Med Sci. 2021 Jan 1;76(1):172-175. doi: 10.1093/gerona/glaa260. PMID: 33045076; PMCID: PMC7756687.
- Ooi DSQ*, Dorajoo R*, Gurung RL, Dehghan R, Lim YY, Ho CWL, Tay V, Karuppiah V, Loke KY, Lim SC, Liu JJ, Sng AA, Lee YS. Association of leukocyte telomere length with obesity-related traits in Asian children with early-onset obesity. Pediatr Obes. 2021 Aug;16(8):e12771. doi: 10.1111/ijpo.12771. Epub 2021 Jan 26. PMID: 33501739.
- Gurung RL*, Dorajoo R*, M Y, Liu JJ, Pek SLT, Wang J, Wang L, Sim X, Liu S, Shao YM, Ang K, Subramaniam T, Tang WE, Sum CF, Liu JJ, Lim SC. Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2021 Jul 13;106(8):2384-2394. doi: 10.1210/clinem/dgab268. PMID: 33889958.
- Dorajoo R, Chang X, Gurung RL, Li Z, Wang L, Wang R, Beckman KB, Adams-Haduch J, M Y, Liu S, Meah WY, Sim KS, Lim SC, Friedlander Y, Liu J, van Dam RM, Yuan JM, Koh WP, Khor CC, Heng CK. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies. Nat Commun. 2019 Jun 6;10(1):2491. doi: 10.1038/s41467-019-10443-2. PMID: 31171785; PMCID: PMC6554354.
- Lu X, Peloso GM, Liu DJ, Wu Y, Zhang H, Zhou W, Li J, Tang CS, Dorajoo R, Li H, Long J, Guo X, Xu M, Spracklen CN, Chen Y, Liu X, Zhang Y, Khor CC, Liu J, Sun L, Wang L, Gao YT, Hu Y, Yu K, Wang Y, Cheung CYY, Wang F, Huang J, Fan Q, Cai Q, Chen S, Shi J, Yang X, Zhao W, Sheu WH, Cherny SS, He M, Feranil AB, Adair LS, Gordon-Larsen P, Du S, Varma R, Chen YI, Shu XO, Lam KSL, Wong TY, Ganesh SK, Mo Z, Hveem K, Fritsche LG, Nielsen JB, Tse HF, Huo Y, Cheng CY, Chen YE, Zheng W, Tai ES, Gao W, Lin X, Huang W, Abecasis G; GLGC Consortium, Kathiresan S, Mohlke KL, Wu T, Sham PC, Gu D, Willer CJ. Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. Nat Genet. 2017 Dec;49(12):1722-1730. doi: 10.1038/ng.3978. Epub 2017 Oct 30. PMID: 29083407; PMCID: PMC5899829.
- Falchi M, El-Sayed Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-Assarsson JC, Sudmant PH, Dorajoo R, Al-Shafai MN, Bottolo L, Ozdemir E, So HC, Davies RW, Patrice A, Dent R, Mangino M, Hysi PG, Dechaume A, Huyvaert M, Skinner J, Pigeyre M, Caiazzo R, Raverdy V, Vaillant E, Field S, Balkau B, Marre M, Visvikis-Siest S, Weill J, Poulain-Godefroy O, Jacobson P, Sjostrom L, Hammond CJ, Deloukas P, Sham PC, McPherson R, Lee J, Tai ES, Sladek R, Carlsson LM, Walley A, Eichler EE, Pattou F, Spector TD, Froguel P. Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet. 2014 May;46(5):492-7. doi: 10.1038/ng.2939. Epub 2014 Mar 30. PMID: 24686848; PMCID: PMC6485469.
- Wen W*, Cho YS*, Zheng W*, Dorajoo R*, Kato N*, Qi L, Chen CH, Delahanty RJ, Okada Y, Tabara Y, Gu D, Zhu D, Haiman CA, Mo Z, Gao YT, Saw SM, Go MJ, Takeuchi F, Chang LC, Kokubo Y, Liang J, Hao M, Le Marchand L, Zhang Y, Hu Y, Wong TY, Long J, Han BG, Kubo M, Yamamoto K, Su MH, Miki T, Henderson BE, Song H, Tan A, He J, Ng DP, Cai Q, Tsunoda T, Tsai FJ, Iwai N, Chen GK, Shi J, Xu J, Sim X, Xiang YB, Maeda S, Ong RT, Li C, Nakamura Y, Aung T, Kamatani N, Liu JJ, Lu W, Yokota M, Seielstad M, Fann CS; Genetic Investigation of ANthropometric Traits (GIANT) Consortium, Wu JY, Lee JY, Hu FB, Tanaka T, Tai ES, Shu XO. Meta-analysis identifies common variants associated with body mass index in east Asians. Nat Genet. 2012 Feb 19;44(3):307-11. doi: 10.1038/ng.1087. PMID: 22344219; PMCID: PMC3288728.