Browsing by Author "Yu, Lei"

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    Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility
    (IOS Press, 2021) Kapasi, Alifiya; Yu, Lei; Stewart, Christopher; Schneider, Julie A.; Bennett, David A.; Boyle, Patricia A.; Neurology, School of Medicine
    Background: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer's disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer's disease (AD) pathology remains unclear. Objective: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. Methods: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. Results: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). Conclusion: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.
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    The Association of Late Life Cognitive Activity with Healthcare and Financial Decision Making in Community-Dwelling, Non-Demented Older Adults
    (Elsevier, 2021) Glover, Crystal M.; Yu, Lei; Stewart, Christopher C.; Wilson, Robert S.; Bennett, David A.; Boyle, Patricia A.; Neurology, School of Medicine
    Objective: The purpose of this study was to test the hypothesis that late life cognitive activity is associated with decision-making in older adults and to examine whether this association varies by level of cognitive function. Design: This study employed a cross-sectional design. Setting: All data were collected in participants' community-based residences. Participants: Participants were 1,084 older adults (mean age = 81.05 years, standard deviation = 7.53) without dementia (median Mini-Mental State Examination score = 29, interquartile range = 27.86-30.00). Measurements: Participants completed assessments of late life cognitive activity, cognitive function, and decision-making. We used linear regression models to examine the associations of late life cognitive activity and cognitive function with decision-making. Results: In a regression model adjusted for age, gender, and education, more frequent late life cognitive activity was associated with better decision-making, as was higher cognitive function. Furthermore, in an additional model that included the interaction of late life cognitive activity and cognitive function, the interaction was significant, such that late life cognitive activity was most strongly associated with decision-making among participants with lower levels of cognitive function. Conclusion: Frequent engagement in late life cognitive activity may help maintain decision-making among older persons, particularly among those with lower levels of cognitive function.
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    Association of TDP-43 Pathology With Domain-specific Literacy in Older Persons
    (Wolters Kluwer, 2019-10-01) Kapasi, Alifiya; Yu, Lei; Stewart, Christopher C.; Schneider, Julie A.; Bennett, David A.; Boyle, Patricia A.; Neurology, School of Medicine
    Background Low health and financial literacy may be an early behavioral manifestation of cognitive impairment, dementia, and accumulating Alzheimer’s pathology. However, there are limited studies investigating the behavioral features associated with hyperphosphorylated transactive response DNA-binding protein-43 (TDP-43), a common age-related pathology, and even fewer studies investigating the neurobiological basis underlying low literacy in aging. Objective To test the hypothesis that TDP-43 pathology is associated with lower literacy. Methods Data came from 293 community-based older persons who were enrolled in two ongoing studies of aging. Participants completed literacy and cognitive assessments, consented to brain donation, and underwent detailed neuropathological evaluation for AD and TDP-43. Linear regression models assessed the association of TDP-43 with literacy after adjusting for demographics, and AD pathology. Post-hoc pairwise comparisons examined whether the level of literacy differed by TDP-43 stage. Results TDP-43 pathology was associated with lower literacy (estimate=−3.16; SE=0.86; p<0.001), above and beyond demographics and AD pathology, and this association persisted even after additionally adjusting for global cognition (estimate=−1.53; SE=0.74; p=0.038). Further, literacy was lower among persons with neocortical TDP-43 pathology compared to those without TDP-43 pathology. Conclusion TDP-43 pathology is associated with lower health and financial literacy in old age, above and beyond AD pathology.
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    Associations of decision making abilities with blood pressure values in older adults
    (Wolters Kluwer, 2020-01-01) Lamar, Melissa; Wilson, Robert S.; Yu, Lei; Stewart, Christopher C.; Bennett, David A.; Boyle, Patricia A.; Neurology, School of Medicine
    Objectives: Decision making, key to successful aging, has implications for financial success, physical health, and well being. While poor decision making has been linked with increased risk of mortality, age-related cognitive decline, and dementia, less is known regarding its associations with chronic disease indicators. We investigated the associations of decision making with blood pressure (BP) values [i.e., SBP, mean arterial pressure (MAP), and pulse pressure (PP), separately] in a community-based cohort study of aging. Methods: Participants were 908 nondemented older adults (age ∼81 years; 75% women) from the Rush Memory and Aging Project. Decision making was measured using questions designed to simulate materials used in financial and healthcare settings in the real world and yielded a total score and domain-specific health and financial decision making scores. Two seated and one standing BP measurement were taken with all three contributing to average SBP, MAP that is, [SBP + (2 × DBP)]/3, and PP, that is, SBP − DBP. Participants were queried about hypertension status and antihypertension medications were visually inspected and coded. Participants also underwent medical history and cognitive assessments. Results: In separate multivariable linear regression models, total decision making scores were inversely associated with SBP, MAP, and PP after adjusting for age, sex, education, antihypertension medication use, diabetes, and cumulative cardiovascular disease burden (P values = 0.03). Decision making remained associated with these BP values after additional adjustment for global cognition. Conclusion: Poorer decision making is associated with higher BP values in nondemented older adults.
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    Associations of Health and Financial Literacy with Mortality in Advanced Age
    (SpringerLink, 2020-05) Stewart, Christopher C.; Yu, Lei; Lamar, Melissa; Wilson, Robert S.; Bennett, David A.; Neurology, School of Medicine
    Background: Health and financial literacy are central to older adults' well-being and financial standing, but the relation of literacy with mortality in advanced age remains unclear. Aims: To determine whether lower literacy, as reflected in measures of total literacy and subscales of health and financial literacy, was associated with an increased risk of mortality. Methods: Participants were 931 community-based older adults from the Rush Memory and Aging Project [age: mean (SD) = 80.9 (7.6), range 58.8-100.8], an ongoing, prospective observational cohort study of aging. Participants were without dementia at the time literacy was assessed. Proportional hazards models were used to determine whether literacy measures were associated with mortality. Results: During up to 8 years of follow-up, 224 (24.1% of 931) participants died. In models that adjusted for age, sex, and education, lower total, health, and financial literacy were each associated with an increased risk of mortality (total literacy: HR = 1.020, 95% CI 1.010-1.031, p < 0.001; health literacy: HR = 1.015, 95% CI 1.008-1.023, p < 0.001; financial literacy: HR = 1.013, 95% CI 1.003-1.023, p = 0.014). These associations persisted after additionally adjusting for income and indices of health status; however, only the association of lower health literacy with mortality persisted after further adjusting for a robust measure of global cognition. Discussion: We suspect that the current associations of lower literacy with mortality reflect the detrimental effect of early pathologic brain aging on literacy. Conclusions: Lower literacy, particularly lower health literacy, is associated with mortality in advanced age.
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    Change in Decision-Making Analysis and Preferences in Old Age
    (Oxford University Press, 2023) Wilson, Robert S.; Yu, Lei; Stewart, Christopher C.; Bennett, David A.; Boyle, Patricia A.; Neurology, School of Medicine
    Objectives: To test the hypotheses that decision making ability declines in old age and that a higher level of cognitive reserve is associated with a reduced rate of decline. Methods: As part of an ongoing cohort study, 982 older adults without dementia at study enrollment completed measures of purpose in life and cognitive activity which were used as markers of cognitive reserve. At annual intervals thereafter, they completed 6 tests of decision making. Results: In a factor analysis of baseline decision making scores, 3 measures (financial/health literacy, financial/health decision making, scam susceptibility) loaded on an "analytic" factor and 3 (temporal discounting small stakes, temporal discounting large stakes, risk aversion) loaded on a "preferences" (for temporal discounting and avoiding risk) factor. During a mean of 4.7 years of follow-up (standard deviation = 2.9), analytic factor scores decreased (mean = 0.042-unit per year, standard error [SE] = 0.006, p < .001) and preferences factor scores increased (mean = 0.021-unit per year, SE = 0.006, p < .001), with a correlation of 0.13 (p < .001) between rates of change. Evidence of an association between cognitive reserve and decision making was mixed with purpose in life related to change in analytic decision making, whereas past (but not current) cognitive activity was related to change in decision making preferences. Discussion: Decision making analysis and preferences change over time in late life. Change over time in decision making components is relatively independent and differentially related to age and cognitive reserve.
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    Childhood Socioeconomic Status Interacts with Cognitive Function to Impact Scam Susceptibility Among Community-Dwelling Older Adults
    (Taylor & Francis, 2023) Glover, Crystal M.; Yu, Lei; Stewart, Christopher C.; Wilson, Robert S.; Bennett, David A.; Lamar, Melissa; Boyle, Patricia A.; Neurology, School of Medicine
    Objectives: We examined whether childhood socioeconomic status (SES) is related to scam susceptibility in old age and tested the hypothesis that childhood SES interacts with cognitive function to impact scam susceptibility. Methods: This study employed a cross-sectional design. All data were collected in participants' community-based residences. Participants were 1071 older adults (mean age = 81.05 years, SD = 7.53) without dementia (median MMSE score = 28.29, IQR = 27.86-30.00). Participants completed assessments of childhood SES, cognitive function, and scam susceptibility. We used linear regression models to examine the associations of childhood SES and cognitive function with scam susceptibility. Results: In a regression model adjusted for age, gender, and education, poorer cognitive function was associated with higher scam susceptibility, but childhood SES was not. However, in an additional model that included the interaction of childhood SES and cognitive function, the interaction was significant, such that lower childhood SES was associated with higher scam susceptibility among participants with lower cognitive function. Conclusion: Lower childhood SES is associated with higher scam susceptibility among older adults with lower levels of cognitive function. Thus, older adults who experienced limited resources in childhood and have lower cognitive function may represent a specific group for interventions to increase scam awareness and prevent financial exploitation.
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    Combined neuropathological pathways account for age-related risk of dementia
    (Wiley, 2018-07) Power, Melinda C.; Mormino, Elizabeth; Soldan, Anja; James, Bryan D.; Yu, Lei; Armstrong, Nicole M.; Bangen, Katherine J.; Delano-Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura; Gross, Alden L.; Mungas, Dan; Widaman, Keith F.; Schneider, Julie; Radiology and Imaging Sciences, School of Medicine
    OBJECTIVE: Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia. METHODS: We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. RESULTS: At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%). INTERPRETATION: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies.
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    Convergent genetic and expression data implicate immunity in Alzheimer's disease
    (Elsevier, 2015-06) Jones, Lesley; Lambert, Jean-Charles; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Vedernikov, Alexey; Escott-Price, Valentina; Stone, Timothy; Richards, Alexander; Bellenguez, Céline; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Gerrish, Amy; Jun, Gyungah; DeStefano, Anita L.; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letteneur, Luc; Kornhuber, Johanes; Tárraga, Lluís; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Emilsson, Valur; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Kehoe, Pat; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleὀ, Alberti; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick; Hardy, John; Naranjo, Maria Candida Deniz; Razquin, Cristina; Bosco, Paola; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Moebus, Susanne; Mecocci, Patrizia; del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R.; Mayhaus, Manuel; Jessen, Frank; Dichgans, Martin; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alavarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee FAG; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John SK; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Pastor, Pau; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, Lindsay A.; van Duijn, Cornelia M.; Van Broekhoven, Christine; Ramirez, Alfredo; Schellenberg, Gerard D.; Seshadri, Sudha; Amouyel, Philippe; Williams, Julie; Holmans, Peter A.; Department of Medical & Molecular Genetics, IU School of Medicine
    Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics.
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    Disentangling the genetics of lean mass
    (Oxford University Press, 2019-02-01) Karasik, David; Zillikens, M. Carola; Hsu, Yi-Hsiang; Aghdassi, Ali; Akesson, Kristina; Amin, Najaf; Barroso, Inês; Bennett, David A.; Bertram, Lars; Bochud, Murielle; Borecki, Ingrid B.; Broer, Linda; Buchman, Aron S.; Byberg, Liisa; Campbell, Harry; Campos-Obando, Natalia; Cauley, Jane A.; Cawthon, Peggy M.; Chambers, John C.; Chen, Zhao; Cho, Nam H.; Choi, Hyung Jin; Chou, Wen-Chi; Cummings, Steven R.; De Groot, Lisette C. P. G. M.; De Jager, Phillip L.; Demuth, Ilja; Diatchenko, Luda; Econs, Michael J.; Eiriksdottir, Gudny; Enneman, Anke W.; Eriksson, Joel; Eriksson, Johan G.; Estrada, Karol; Evans, Daniel S.; Feitosa, Mary F.; Fu, Mao; Gieger, Christian; Grallert, Harald; Gudnason, Vilmundur; Lenore, Launer J.; Hayward, Caroline; Hofman, Albert; Homuth, Georg; Huffman, Kim M.; Husted, Lise B.; Illig, Thomas; Ingelsson, Erik; Ittermann, Till; Jansson, John-Olov; Johnson, Toby; Biffar, Reiner; Jordan, Joanne M.; Jula, Antti; Karlsson, Magnus; Khaw, Kay-Tee; Kilpeläinen, Tuomas O.; Klopp, Norman; Kloth, Jacqueline S. L.; Koller, Daniel L.; Kooner, Jaspal S.; Kraus, William E.; Kritchevsky, Stephen; Kutalik, Zoltán; Kuulasmaa, Teemu; Kuusisto, Johanna; Laakso, Markku; Lahti, Jari; Lang, Thomas; Langdahl, Bente L.; Lerch, Markus M.; Lewis, Joshua R.; Lill, Christina; Lind, Lars; Lindgren, Cecilia; Liu, Yongmei; Livshits, Gregory; Ljunggren, Östen; Loos, Ruth J. F.; Lorentzon, Mattias; Luan, Jian'an; Luben, Robert N.; Malkin, Ida; McGuigan, Fiona E.; Medina-Gomez, Carolina; Meitinger, Thomas; Melhus, Håkan; Mellström, Dan; Michaëlsson, Karl; Mitchell, Braxton D.; Morris, Andrew P.; Mosekilde, Leif; Nethander, Maria; Newman, Anne B.; O'Connell, Jeffery R.; Oostra, Ben A.; Orwoll, Eric S.; Palotie, Aarno; Peacock, Munro; Perola, Markus; Peters, Annette; Prince, Richard L.; Psaty, Bruce M.; Räikkönen, Katri; Ralston, Stuart H.; Ripatti, Samuli; Rivadeneira, Fernando; Robbins, John A.; Rotter, Jerome I.; Rudan, Igor; Salomaa, Veikko; Satterfield, Suzanne; Schipf, Sabine; Shin, Chan Soo; Smith, Albert V.; Smith, Shad B.; Soranzo, Nicole; Spector, Timothy D.; Stančáková, Alena; Stefansson, Kari; Steinhagen-Thiessen, Elisabeth; Stolk, Lisette; Streeten, Elizabeth A.; Styrkarsdottir, Unnur; Swart, Karin M. A.; Thompson, Patricia; Thomson, Cynthia A.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Tranah, Gregory J.; Uitterlinden, André G.; Van Duijn, Cornelia M.; Van Schoor, Natasja M.; Vandenput, Liesbeth; Vollenweider, Peter; Völzke, Henry; Wactawski-Wende, Jean; Walker, Mark; Wareham, Nicholas J.; Waterworth, Dawn; Weedon, Michael N.; Wichmann, H-Erich.; Widen, Elisabeth; Williams, Frances M. K.; Wilson, James F.; Wright, Nicole C.; Yerges-Armstrong, Laura M.; Yu, Lei; Zhang, Weihua; Zhao, Jing Hua; Zhou, Yanhua; Nielson, Carrie M.; Harris, Tamara B.; Demissie, Serkalem; Kiel, Douglas P.; Ohlsson, Claes; Medicine, School of Medicine
    Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.