Publications by authors named "Mary K Wojczynski"

77 Publications

Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior.

J Alzheimers Dis 2021 ;82(1):17-32

Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA.

Background: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition.

Objective: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST).

Methods: A subset of Long Life Family Study participants (n = 1,594) completed the DSST. Total time to draw each symbol was divided into 'writing' and non-writing or 'thinking' time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores.

Results: Clustering revealed four 'thinking' time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of 'writing' time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores.

Conclusion: Digital data identified previously unrecognized patterns of 'writing' and 'thinking' time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions.
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http://dx.doi.org/10.3233/JAD-201119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328075PMC
September 2021

Identification of a Novel Locus for Gait Speed Decline With Aging: The Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e307-e313

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania, USA.

Background: Gait speed is a powerful indicator of health with aging. Potential genetic contributions to gait speed and its decline with aging are not well defined. We determined the heritability of and potential genetic regions underlying change in gait speed using longitudinal data from 2379 individuals belonging to 509 families in the Long Life Family Study (mean age 64 ± 12, range 30-110 years; 45% men).

Methods: Gait speed was measured over 4 m at baseline and follow-up (7 ± 1 years). Quantitative trait linkage analyses were completed using pedigree-based maximum likelihood methods with logarithm of the odds (LOD) scores greater than 3.0, indicating genome-wide significance. We also performed linkage analysis in the top 10% of families contributing to LOD scores to allow for heterogeneity among families (HLOD). Data were adjusted for age, sex, height, and field center.

Results: At baseline, 26.9% of individuals had "slow" gait speed less than 1.0 m/s (mean: 1.1 ± 0.2 m/s) and gait speed declined at a rate of -0.02 ± 0.03 m/s per year (p < .0001). Baseline and change in gait speed were significantly heritable (h2 = 0.24-0.32, p < .05). We did not find significant evidence for linkage for baseline gait speed; however, we identified a significant locus for change in gait speed on chromosome 16p (LOD = 4.2). A subset of 21 families contributed to this linkage peak (HLOD = 6.83). Association analyses on chromosome 16 showed that the strongest variant resides within the ADCY9 gene.

Conclusion: Further analysis of the chromosome 16 region, and ADCY9 gene, may yield new insight on the biology of mobility decline with aging.
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http://dx.doi.org/10.1093/gerona/glab177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436996PMC
September 2021

Heterogeneity of the Predictive Polygenic Risk Scores for Coronary Heart Disease Age-at-Onset in Three Different Coronary Heart Disease Family-Based Ascertainments.

Circ Genom Precis Med 2021 Jun 12;14(3):e003201. Epub 2021 Apr 12.

Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO (M.F.F., M.K.W., L.W., M.A.P.).

Background: Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly.

Methods: Our study included 3 family-based ascertainments: LLFS (Long Life Family Study, N=4572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-random, N=1806), and high CHD risk families (FamHS-high risk, N=2301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-high risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models.

Results: Healthy-aging LLFS presented ≈17 years delayed for CHD age-at-onset compared with FamHS-high risk (1.0×10). Sex-specific association (<1.0×10) and PRS*sex (=2.7×10) predicted prevalent CHD. CHD age-at-onset was associated with PRS (hazard ratio [HR], 1.57; =1.3×10), LLFS (HR, 0.54; =2.6×10), and FamHS-high risk (HR, 2.86; =6.70x10) in men, and with PRS (HR, 1.76; =7.70×10), FamHS-high risk (HR, 4.88; =8.70×10), and PRS×FamHS-high risk (HR, 0.61; =3.60×10) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated (<0.05) with PRS, FamHS-high risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution.

Conclusions: Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD end points at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.
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http://dx.doi.org/10.1161/CIRCGEN.120.003201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214825PMC
June 2021

Genetic association analysis of the cardiovascular biomarker: N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP).

PLoS One 2021 15;16(3):e0248726. Epub 2021 Mar 15.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, United States of America.

Background: NT-proBNP is a biomarker of cardiovascular disease (CVD). Little is known about the heritability and genetic variants associated with NT-proBNP. Therefore, we estimated the heritability of and examined genetic associations of SNPs in the BNP gene region with circulating NT-proBNP and prevalent CVD in 4,331 participants from the Long Life Family Study (LLFS).

Methods And Results: Genotypes of 10 SNPs from the NPPB and NPPA regions that encode BNP and A-type natriuretic peptide, respectively, were tested for association with NT-proBNP and prevalent cardiovascular disease and risk factors. We performed analyses using the Sequential Oligogenic Linkage Analysis (SOLAR) program to account for family relatedness, and adjusted all models for age, sex, and field center. The mean age of the LLFS was 69.8 years (range 24-110) with 55.4% females. NT-proBNP was significantly heritable (h2 = 0.21; P = 4x10-14), and the minor alleles of rs632793 (p<0.001) and rs41300100 (p = 0.05) were independently associated with higher serum NT-proBNP levels. Additionally, the minor allele of rs632793 was significantly and consistently associated with lower prevalent CVD, including blood pressures, independent of NT-proBNP level (all P<0.05). Results for prevalent CVD, but not NT-proBNP levels, showed significant interaction by familial generation.

Conclusion: In this family-based study of subjects with exceptional longevity, we identified several allelic variants in the BNP gene region associated with NT-pro-BNP levels and prevalent CVD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248726PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959346PMC
October 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

Nat Commun 2021 01 28;12(1):654. Epub 2021 Jan 28.

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
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http://dx.doi.org/10.1038/s41467-021-20918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844411PMC
January 2021

Relationship Between Serum IGF-1 and BMI Differs by Age.

J Gerontol A Biol Sci Med Sci 2021 06;76(7):1303-1308

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pennsylvania.

Background: Serum levels of insulin-like growth factor 1 (IGF-1) and body mass index (BMI) are both associated with susceptibility to age-related diseases. Reports on the correlation between them have been conflicting, with both positive to negative correlations reported. However, the age ranges of the participants varied widely among these studies.

Methods: Using data on 4241 participants (aged 24-110) from the Long Life Family Study, we investigated the relationship between IGF-1 and BMI by age groups using regression analysis.

Results: When stratified by age quartile, the relationship between IGF-1 and BMI varied: in the first quartile (Q1, 20-58 years) the relationship was negative (β = -0.2, p = .002); in Q2 (58-66 years) and Q3 (67-86 years) the relationship was negative (β = -0.07, β = -0.01, respectively) but nonsignificant; and in Q4 (87-110 years) the relationship was positive (β = 0.31, p = .0002). This pattern did not differ by sex. We observed a similar age-related pattern between IGF-1 and BMI among participants in the third National Health and Nutritional Examination Survey.

Conclusions: Our results that the relationship between IGF-1 and BMI differs by age may explain some of the inconsistency in reports about their relationship and encourage additional studies to understand the mechanisms underlying it.
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http://dx.doi.org/10.1093/gerona/glaa282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202150PMC
June 2021

Evaluation of the Bidirectional Relations of Perceived Physical Fatigability and Physical Activity on Slower Gait Speed.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e237-e244

Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Lower physical activity levels and greater fatigability contribute independently to slower gait speed in older adults. To fully understand the bidirectional relations between physical activity and fatigability, and to inform potential intervention strategies, we examined whether physical activity or fatigability explains more of the other factor's association on slower gait speed.

Methods: Two generations (probands and offspring) of older adults (N = 2079, mean age 73.0 ± 10.0 years, 54.2% women, 99.7% White) enrolled in the Long Life Family Study were assessed at Visit 2 (2014-2017). Self-reported physical activity was measured with the Framingham Physical Activity Index and perceived physical fatigability using the Pittsburgh Fatigability Scale. Statistical mediation analyses were conducted separately by generation with linear mixed-effect models accounting for family relatedness and adjusted for demographics, health conditions, and field center.

Results: Greater perceived physical fatigability explained the association of lower physical activity on slower gait speed via a 22.5% attenuation of the direct association (95% confidence interval [CI]: 15.0%-35.2%) for the probands and 39.5% (95% CI: 22.8%-62.6%) for the offspring. Whereas lower physical activity explained the association of greater perceived fatigability on slower gait speed via a 22.5% attenuation of the direct association (95% CI: 13.4%-32.8%) for the probands and 6.7% (95% CI: 3.8%-15.4%) for the offspring.

Conclusions: Our findings suggest that the impact of greater perceived physical fatigability on the association between lower physical activity and slower gait speed differs between younger-old and middle-to-oldest-old adults, indicating perceived physical fatigability as a potential mediator in the disablement pathway.
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http://dx.doi.org/10.1093/gerona/glaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436994PMC
September 2021

Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study.

Aging Cell 2020 10 4;19(10):e13228. Epub 2020 Sep 4.

Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.

The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival.
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http://dx.doi.org/10.1111/acel.13228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576291PMC
October 2020

Circulating Procollagen Type III N-Terminal Peptide and Physical Function in Adults from the Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2021 06;76(7):1273-1279

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania.

Background: Circulating levels of procollagen type III N-terminal peptide (P3NP) may reflect increased fibrosis of skeletal muscle and other tissues with aging. Herein, we tested if P3NP was associated with baseline and 7-year change in physical function.

Method: Participants (n = 400) were from the Long Life Family Study, a study of exceptional familial longevity. Plasma P3NP concentration was measured using a sandwich enzyme-linked immunosorbent assay (inter-assay coefficient of variation <5.5%). At baseline and 7-year follow-up visits, physical function was measured using the Short Physical Performance Battery (SPPB score 0-12), which consists of gait speed, balance, and chair-rise tests. Grip strength was measured using a handheld dynamometer. The association between log-transformed P3NP and physical function was examined using generalized estimating equations adjusted for familial relatedness, age, sex, height, weight, lifestyle characteristics, liver function, kidney function, lung function, and chronic disease prevalence.

Results: Participants were aged 73.1 ± 15.2 years (range: 39-104), 54% female, had body mass index of 26.6 ± 4.3 kg/m2, and gait speeds of 1.0 ± 0.3 m/s. One standard deviation higher log-transformed P3NP was related to worse baseline SPPB score (β = -0.9points), gait speed (β = -0.05m/s), chair-rises per-second (β = -0.46chair-rises/10 seconds), and grip strength (β = -2.0kg; all p < .001). Higher P3NP was also associated with greater declines in gait speed (β = -1.41, p < .001) and transitioning to being unable to perform chair-rises (β = 0.41, p < .001) after 7 years.

Conclusion: Plasma P3NP may be a strong, novel biomarker of current and future physical function. Future research is needed to extend our findings to other cohorts and determine mechanisms underlying these associations.
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http://dx.doi.org/10.1093/gerona/glaa197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355442PMC
June 2021

Prevalence of clinically actionable disease variants in exceptionally long-lived families.

BMC Med Genomics 2020 04 10;13(1):61. Epub 2020 Apr 10.

Department of Laboratory Medicine and Pathology, University of Minnesota, MMC 609, 420 Delaware street, Minneapolis, MN, 55455, USA.

Background: Phenotypic expression of pathogenic variants in individuals with no family history of inherited disorders remains unclear.

Methods: We evaluated the prevalence of pathogenic variants in 25 genes associated with Mendelian-inherited disorders in 3015 participants from 485 families in the Long Life Family Study (LLFS). Boot-strapping and Fisher's exact test were used to determine whether allele frequencies in LLFS were significantly different from the allele frequencies reported in publicly available genomic databases.

Results: The proportions of pathogenic autosomal dominant mutation carriers in BRCA1 and SDHC in LLFS study participants were similar to those reported in publicly available genomic databases (0.03% vs. 0.0008%, p = 1 for BRCA1, and 0.08% vs. 0.003%, p = 0.05 for SDHC). The frequency of carriers of pathogenic autosomal recessive variants in CPT2, ACADM, SUMF1, WRN, ATM, and ACADVL were also similar in LLFS as compared to those reported in genomic databases. The lack of clinical disease among LLFS participants with well-established pathogenic variants in BRCA1 and SDHC suggests that penetrance of pathogenic variants may be different in long lived families.

Conclusion: Further research is needed to better understand the penetrance of pathogenic variants before expanding large scale genomic testing to asymptomatic individuals.
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http://dx.doi.org/10.1186/s12920-020-0710-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146901PMC
April 2020

Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies.

Atherosclerosis 2020 03 14;297:102-110. Epub 2020 Feb 14.

Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.

Backgrounds And Aims: Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change.

Methods: We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies.

Results: We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways.

Conclusions: Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098811PMC
March 2020

Epidemiology of Perceived Physical Fatigability in Older Adults: The Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2020 09;75(9):e81-e88

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Fatigability is a construct that measures whole-body tiredness anchored to activities of a fixed intensity and duration; little is known about its epidemiology and heritability.

Methods: Two generations of family members enriched for exceptional longevity and their spouses were enrolled (2006-2009) in the Long Life Family Study (LLFS). At Visit 2 (2014-2017, N = 2,355) perceived physical fatigability was measured using the 10-item self-administered Pittsburgh Fatigability Scale (PFS), along with demographic, medical, behavioral, physical, and cognitive risk factors.

Results: Residual genetic heritability of fatigability was 0.263 (p = 6.6 × 10-9) after adjustment for age, sex, and field center. PFS physical scores (mean ± SD) and higher physical fatigability prevalence (% PFS ≥ 15) were greater with each age strata: 60-69 (n = 1,009, 11.0 ± 7.6, 28%), 70-79 (n = 847, 12.5 ± 8.1, 37%), 80-89 (n = 253, 19.3 ± 9.9, 65.2%), and 90-108 (n = 266, 28.6 ± 9.8, 89.5%), p < .0001, adjusted for sex, field center, and family relatedness. Women had a higher prevalence of perceived physical fatigability compared to men, with the largest difference in the 80-89 age strata, 74.8% versus 53.5%, p < .0001. Those with greater body mass index, worse physical and cognitive function, and lower physical activity had significantly higher perceived physical fatigability.

Conclusions: Perceived physical fatigability is highly prevalent in older adults and strongly associated with age. The family design of LLFS allowed us to estimate the genetic heritability of perceived physical fatigability. Identifying risk factors associated with higher perceived physical fatigability can inform the development of targeted interventions for those most at risk, including older women, older adults with depression, and those who are less physically active.
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http://dx.doi.org/10.1093/gerona/glz288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494027PMC
September 2020

Genome-wide linkage analysis of carotid artery traits in exceptionally long-lived families.

Atherosclerosis 2019 12 10;291:19-26. Epub 2019 Oct 10.

Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.

Background And Aims: Atherosclerosis develops with age and is partially controlled by genetics. Research to date has identified common variants with small effects on atherosclerosis related traits. We aimed to use family-based genome-wide linkage analysis to identify chromosomal regions potentially harboring rare variants with larger effects for atherosclerosis related traits.

Methods: Participants included 2205 individuals from the Long Life Family Study (LLFS), which recruited families with exceptional longevity from Boston, New York, Pittsburgh, and Denmark. Participants underwent B-mode ultrasonography of the carotid arteries to measure intima-media thickness (IMT), inter-adventitial diameter (IAD), and plaque presence and severity. We conducted residual heritability and genome-wide linkage analyses adjusted for age, age, sex, and field center using pedigree-based maximum-likelihood methods in SOLAR.

Results: All carotid traits were significantly heritable with a range of 0.68 for IAD to 0.38 for IMT. We identified three chromosomal regions with linkage to IAD (3q13; max LOD 5.3), plaque severity (17q22-q23, max LOD 3.2), and plaque presence (17q24, max LOD 3.1). No common allelic variants within these linkage peaks were associated with the carotid artery traits.

Conclusions: We identified three chromosomal regions with evidence of linkage to carotid artery diameter and atherosclerotic plaque in exceptionally long-lived families. Since common allelic variants within our linkage peaks did not account for our findings, future follow-up resequencing of these regions in LLFS families should help advance our understanding of atherosclerosis, CVD, and healthy vascular aging.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899182PMC
December 2019

A meta-analysis of genome-wide association studies identifies multiple longevity genes.

Nat Commun 2019 08 14;10(1):3669. Epub 2019 Aug 14.

Department of Public Health, University of Southern Denmark, 5000, Odense C, Denmark.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.
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http://dx.doi.org/10.1038/s41467-019-11558-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694136PMC
August 2019

Heterogeneity of healthy aging: comparing long-lived families across five healthy aging phenotypes of blood pressure, memory, pulmonary function, grip strength, and metabolism.

Geroscience 2019 08 22;41(4):383-393. Epub 2019 Jul 22.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 5126 Public Health, 130 DeSoto Street, Pittsburgh, PA, 15261, USA.

Five healthy aging phenotypes were developed in the Long Life Family Study to uncover longevity pathways and determine if healthy aging across multiple systems clustered in a subset of long-lived families. Using blood pressure, memory, pulmonary function, grip strength, and metabolic measures (body mass index, waist circumference and fasting levels of glucose, insulin, triglycerides, lipids, and inflammatory markers), offspring were ranked according to relative health using gender-, age-, and relevant confounder-adjusted z-scores. Based on our prior work, families met a healthy aging phenotype if ≥ 2 and ≥ 50% of their offspring were exceptionally healthy for that respective phenotype. Among 426 families, only two families met criteria for three healthy aging phenotypes and none met criteria for four or more healthy aging phenotypes. Using Spearman correlation, the proportion of offspring within families with exceptionally healthy pulmonary function was correlated with the proportion of offspring within families with exceptional strength (r = 0.19, p = 0.002). The proportion of offspring within families meeting the healthy blood pressure and metabolic phenotypes were also correlated (r = 0.14, p = 0.006), and more families were classified as meeting healthy blood pressure and metabolic phenotypes (Kappa = 0.10, p = 0.02), as well as the healthy pulmonary and blood pressure phenotypes than expected by chance (Kappa = 0.09, p = 0.03). Other phenotypes were weakly correlated (|r| ≤ 0.07) with low pairwise agreement (Kappa ≤ 0.06). Among these families selected for familial longevity, correspondence between healthy aging phenotypes was weak, supporting the heterogeneous nature of longevity and suggesting biological underpinnings of each individual phenotype should be examined separately to determine their shared and unique determinants.
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http://dx.doi.org/10.1007/s11357-019-00086-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815318PMC
August 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2020 04;75(5):899-905

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pennsylvania.

Background: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation.

Methods: We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication.

Results: At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05).

Conclusions: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.
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http://dx.doi.org/10.1093/gerona/glz124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164521PMC
April 2020

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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http://dx.doi.org/10.1038/s41588-019-0378-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467258PMC
April 2019

A novel healthy metabolic phenotype developed among a cohort of families enriched for longevity.

Metabolism 2019 05 30;94:28-38. Epub 2019 Jan 30.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Departments of Medicine and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Background: Long-lived individuals and their offspring have healthier metabolic characteristics than expected, such as more favorable levels of fasting glucose, insulin, and lipids than controls without longevity. Dysregulation in metabolic pathways has also shown to predict accelerated aging. Using information from the Long Life Family Study (LLFS), a multi-center study of two-generation families selected for exceptional longevity, we developed an indicator of healthy metabolism to determine whether metabolic health was more prevalent in a subset of LLFS families and whether it was heritable and associated with other metrics of healthy aging.

Methods: A Latent Profile Analysis was applied to age- and gender-adjusted z-scores of fasting levels of glucose, insulin, triglycerides, and high-density lipoprotein cholesterol, body mass index, waist circumference, interleukin-6, and C-reactive protein. Families were defined as meeting the healthy metabolic phenotype if ≥2 and ≥50% of their offspring were classified into a latent subgroup with a profile of healthier metabolic markers than expected given age and gender relative to all LLFS offspring.

Results: The log odds of being classified into the latent subgroup with a healthy profile of metabolic markers was heritable (h = 0.40, p < 0.001). Among 388 families, 39 (10%) met the healthy metabolic phenotype. Participants from these families had somewhat better cognition than those from remaining families. Proband-generation participants from families who met the healthy metabolic phenotype also had better pulmonary functioning and physical performance.

Conclusions: The better cognition, pulmonary function, and physical performance among probands from families with the healthy metabolic phenotype may indicate that this subset of LLFS families have a more extreme longevity phenotype than other LLFS families since cognitive, physical, and pulmonary function are top mortality predictors for older adults. Future work is needed to determine if rare or protective alleles confer a healthy metabolic phenotype in this subset of LLFS families with exceptional metabolism.
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http://dx.doi.org/10.1016/j.metabol.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099575PMC
May 2019

Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.

Am J Epidemiol 2019 06;188(6):1033-1054

Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.

A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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http://dx.doi.org/10.1093/aje/kwz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545280PMC
June 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
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http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019

The APOE ε4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study.

PLoS One 2018 9;13(11):e0206873. Epub 2018 Nov 9.

Laboratory of Asthma and Lung Inflammation, Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, United States of America.

Introduction: Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function.

Objectives: We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study.

Methods: Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ε2, ε3, and ε4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ε2 allele, defined as ε2/2 or ε2/3 genotypes, and the ε4 allele, defined as ε3/4 or ε4/4 genotypes, which were compared to the ε3/3 genotype.

Results: The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ε4 allele as compared to women with the ε3/3 genotype or the ε2 allele. Carriage of the APOE ε4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease.

Conclusions: This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ε4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206873PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226172PMC
April 2019

Genetics of Human Longevity From Incomplete Data: New Findings From the Long Life Family Study.

J Gerontol A Biol Sci Med Sci 2018 10;73(11):1472-1481

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina.

The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.
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http://dx.doi.org/10.1093/gerona/gly057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175028PMC
October 2018

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Nat Commun 2018 07 30;9(1):2976. Epub 2018 Jul 30.

University of California Los Angeles, Los Angeles, CA, 90095, USA.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.
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http://dx.doi.org/10.1038/s41467-018-05369-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065313PMC
July 2018

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Mol Psychiatry 2019 12 9;24(12):1920-1932. Epub 2018 Jul 9.

Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
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http://dx.doi.org/10.1038/s41380-018-0079-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326896PMC
December 2019

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

PLoS One 2018 18;13(6):e0198166. Epub 2018 Jun 18.

Icelandic Heart Association, Kopavogur, Iceland.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005576PMC
January 2019

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

Am J Hum Genet 2018 03 15;102(3):375-400. Epub 2018 Feb 15.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD 21224, USA.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
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http://dx.doi.org/10.1016/j.ajhg.2018.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985266PMC
March 2018
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