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Biomedical subjects

Jaakko Kaprio

Publications and source records attributed to Jaakko Kaprio.

At least 19 recordsLinked to original sources

Genome-wide association meta-analysis of eating behavior traits revealed one susceptibility locus for emotional eating.

In order to identify new and genome-wide significant loci for eating behavior traits (cognitive restraint, uncontrolled eating and emotional eating), we conducted a meta-GWAS with seven studies of European ancestry (n&#x2009;=&#x2009;11,250). Eating behavior was assessed using the Three-Factor Eating Questionnaire. Genotype effects of single studies were estimated using additive models adjusting for age, sex, BMI, and principal components and single study results were combined by fixed-effect meta-analysis.For cognitive restraint and uncontrolled eating, no genome-wide significant association could be detected. For emotional eating, one genomic region on chromosome 5 comprising two polymorphisms attained genome-wide significance (P&#x2009;=&#x2009;4.0&#xd7;10-8 for rs6877636 and P&#x2009;=&#x2009;3.2&#xd7;10-8 for rs6897090). The minor alleles were associated with higher emotional eating scores (&#x3b2;=0.093&#x2009;&#xb1;&#x2009;0.017), with a similar direction of effect in each study. Both SNPs, in near perfect linkage disequilibrium, mapped to RP11-24P24.1, a processed pseudogene of ornithine decarboxylase 1 (ODC1). Enrichment analysis revealed a significant overlap between genome-wide BMI-associated variants and nominal emotional eating variants, supporting the hypothesis that shared genetic factors may influence both eating behavior traits and obesity risk. Finally, we observed a number of interesting associations reaching suggestive significance (P&#x2009;<&#x2009;10-6) involving BMI candidate genes, including a suggestive association between FTO variants and cognitive restraint (rs9922708, &#x3b2;&#x2009;=&#x2009;0.069, P&#x2009;=&#x2009;5.9&#xd7;10-7).In conclusion, our meta-GWAS identified for the first time a robust chromosomal region associated with emotional eating in seven studies. Given that emotional eating strongly influences body weight but is often stigmatized, recognizing genetic susceptibility to certain eating behaviors may help reduce stigma and alleviate guilt.

Journal Article↗

Robust inference and correlates from genetic associations with personality.

Personality traits describe stable differences in how people think, feel and behave, and how they interact with and experience their social and physical environments1,2. Many questions remain unanswered about associations between DNA and personality traits, such as their robustness, their&#xa0;generalizability and the biological and social pathways through which they act. Here we meta-analyse data across 46 cohorts comprising 611,037 to 1.14&#x2009;million participants with European-like and African-like genomes for genome-wide association studies (GWAS) of the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism and openness to experience), and data from up to 50,725 participants for within-family GWAS. We identify 1,260 lead genetic variants associated with personality, including 824 novel variants3. Common genetic variants explain a moderate 4.8-9.3% of the variance in measures of each trait, and 9.3-13.3% among instruments with typical measurement reliability. Genetic associations with personality are highly consistent but not identical across geography, reporter (self versus close other), age group and measurement instrument, and we find minimal spousal assortment for personality in recent history. In contrast to many other social and behavioural traits4,5, within-family GWAS and polygenic index analyses indicate that genetic associations with personality are minimally confounded by the shared family environment. Polygenic prediction, genetic correlation and Mendelian randomization analyses indicate that personality traits have widespread, potentially causal associations with consequential behaviours and life outcomes. Overall, we find that the genetic architecture of personality is robustly generalizable, minimally confounded and widely relevant to human experience.

Journal Article↗

Evaluating a Genome-Wide Polygenic Score for Handgrip Strength and Its Interplay with Leisure-Time Physical Activity Across the IGEMS Twin Cohorts.

PURPOSE: Polygenic scores (PGSs) may help assess genetic predisposition to multifactorial traits. We examined whether age, sex, and leisure-time physical activity (LTPA) modify the association between a PGS for handgrip strength (HGS) and measured HGS in older adults. METHODS: PGS for HGS (PGS hgs) , based on Pan-UK Biobank genome-wide association study data, was calculated for 5103 participants (aged 40-96; 44% women) from eight twin cohorts in Denmark, Sweden, Australia, the United States, and Finland within the IGEMS consortium. Sex-standardized HGS and self-reported LTPA were assessed cross-sectionally. Linear mixed models estimated associations between PGS hgs and HGS, including interactions with age, country, and LTPA, as well as an association between PGS hgs and LTPA. Fixed-effect within-pair models were conducted to assess environmental contributions. RESULTS: Higher PGS hgs was associated with greater HGS (&#x3b2; = 2.14, SE = 0.15, P < 0.001), explaining 4.6% of HGS variance overall, with modest variation across countries. In sex-stratified models, PGS hgs explained 5.2% of the variance in females and 4.3% in males. No statistically significant interaction with age was found. A significant PGS hgs &#xd7; LTPA interaction (&#x3b2; = -0.034, P = 0.013) indicated that the association between LTPA and HGS was more pronounced among individuals with lower PGS hgs . The within-pair models offered limited support for the independent environmental impact of LTPA. CONCLUSIONS: The PGS hgs was associated with measured HGS in the meta-analysis, highlighting the potential of PGSs to capture individual differences in strength-related traits across populations. The association of PGS hgs with HGS was moderated by LTPA, such that the beneficial impact of LTPA on HGS was greater among individuals with a lower genetic propensity for HGS.

Humans↗

Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas.

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Atlases as Topic↗

Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins.

Exercise is considered to be beneficial for free fatty acid (FFA) metabolism, although reports of the effects of increased physical activity on FFA uptake and oxidation in different tissues in vivo in humans have been inconsistent. To investigate the heredity-independent effects of physical activity and fitness on FFA uptake in skeletal muscle, the myocardium, and liver we used positron emission tomography (PET) in nine healthy young male monozygotic twin pairs discordant for physical activity and fitness. The cotwins with higher physical activity constituting the more active group had a similar body mass index but less body fat and 18 +/- 10% higher (P < 0.001) compared to the less active brothers with lower physical activity. Low-intensity knee-extension exercise increased skeletal muscle FFA and oxygen uptake six to 10 times compared to resting values but no differences were observed between the groups at rest or during exercise. At rest the more active group had lower hepatic FFA uptake compared to the less active group (5.5 +/- 4.3 versus 9.0 +/- 6.1 micromol (100 ml)(-1) min(-1), P = 0.04). Hepatic FFA uptake associated significantly with body fat percentage (P = 0.05). Myocardial FFA uptake was similar between the groups. In conclusion, in the absence of the confounding effects of genetic factors, moderately increased physical activity and aerobic fitness decrease body adiposity even in normal-weighted healthy young adult men. Further, increased physical activity together with decreased intra-abdominal adiposity seems to decrease hepatic FFA uptake but has no effects on skeletal muscle or myocardial FFA uptake.

Adipose Tissue↗

The relationship between performance and fMRI signal during working memory in patients with schizophrenia, unaffected co-twins, and control subjects.

While behavioral research shows working memory impairments in schizophrenics and their relatives, functional neuroimaging studies of patients and healthy controls show conflicting findings of hypo- and hyperactivation, possibly indicating different relationships between physiological activity and performance. In a between-subjects regression analysis of fMRI activation and performance, low performance was associated with relatively lower activation in patients than controls, while higher performance was associated with higher activation in patients than controls in DLPFC and parietal cortex, but not occipital cortex, with unaffected twins of schizophrenics being intermediate between the groups. Accordingly, this supports the idea that both hyper and hypoactivation may be possible along a continuum of behavioral performance in a way consistent with a neural inefficiency model. Further, this study offers preliminary evidence that the relationship between behavior and physiology in schizophrenia may be heritable.

Aged↗

Genetic and environmental factors affecting self-rated health from age 16-25: a longitudinal study of Finnish twins.

We analyzed genetic and environmental determinants of self-rated health and its change from adolescence to early adulthood. Questionnaires were mailed to Finnish twins born 1975-1979 at ages 16, 17, 18 1/2 and, on average, 25 years of age (N=2465 complete twin pairs). The data were analyzed using quantitative genetic methods for twin data by the Mx statistical package. Heritability of self-rated health was greatest at age 16 (63%, 95% confidence intervals (CI) 56-67%, men and women together) and declined steadily to age 25 (33%, 95% CI 25-41%). The residual variation was due to unshared environments. Health ratings at different ages were modestly correlated (r=0.33-0.61). These correlations were mainly due to genetic factors, but unshared environment also contributed to them. An important challenge for further research is to identify environmental influences contributing to self-rated health independently of, or in interaction with, genetic factors.

Adolescent↗

Inherited auditory-cortical dysfunction in twin pairs discordant for schizophrenia.

BACKGROUND: Information on the inheritance of neurophysiological abnormalities might help elucidate the molecular genetic basis of schizophrenia. We used magnetoencephalography (MEG) and electroencephalography (EEG) to investigate the inheritance of auditory-cortical deficiencies in twin pairs discordant for schizophrenia. METHODS: Auditory EEG/MEG responses to frequent standard and occasional deviant tones were measured in mono- and dizygotic (MZ and DZ) twin pairs discordant for schizophrenia and demographically matched healthy twin pairs, recruited from a total population cohort. The MEG/EEG results were regressed against the genetic resemblance to patients with schizophrenia across the patients' unaffected MZ/DZ co-twins and control subjects (with genetic correlations of 1, .5, and 0 to schizophrenia patients, respectively). RESULTS: The EEG responses P50, N100, and mismatch negativity (MMN), as well as the MEG response P50m, were reduced in the schizophrenic patients. P50 and N100 were significantly decreased also in their unaffected co-twins, as compared with the control subjects. Importantly, the P50 and N100 decrease correlated with the unaffected subjects' genetic resemblance to schizophrenia patients. CONCLUSIONS: Our results suggest inherited abnormalities in cortical auditory processing in schizophrenia, reflected by the decreased P50/P50m and N100 amplitudes, whereas the MMN abnormalities might reflect predominantly state-dependent neurodegeneration.

Brain Mapping↗

Minor depression in adolescence: phenomenology and clinical correlates.

BACKGROUND: Depressions that fail to meet the diagnostic criteria for major depressive disorder (MDD) may be underdiagnosed and undertreated in adolescent population. Traditionally, they are not considered as serious conditions and the phenomenological nature and clinical correlates of these disorders are largely unknown. In the present study, we used a large, representative and age-standardized sample of adolescents to examine the phenomenology and clinical correlates of minor depression, a poorly understood condition included in the category of Depressive Disorder Not Otherwise Specified in Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revised (DSM-IV-TR). METHODS: 909 girls and 945 boys, with mean age of 14, were interviewed by professionals using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). RESULTS: Although clearly milder condition than MDD, minor depression was associated with marked suicidal thoughts, plans and attempts, recurrences and a high degree of comorbidity. At this early age, despite that 14% of adolescents under 15 had suffered from depressive conditions with severe clinical implications, most of them failing to meet the diagnostic threshold for MDD, only 1.7% had received any psychiatric treatment. 40% of depressive adolescents who had attempted suicide had no contact with mental health services. LIMITATIONS: Analyzed in a cross-sectional setting, no conclusions about long-term implications could be made. CONCLUSIONS: The results highlight the clinical and public health significance of non-MDD depressions, e.g. minor depression, which need to be more carefully identified and treated at early age.

Adolescent↗

Relationship between local perfusion and FFA uptake in human skeletal muscle-no effect of increased physical activity and aerobic fitness.

We investigated heredity-independent effects of increased physical activity and aerobic fitness on skeletal muscle free fatty acid (FFA) uptake, perfusion, and their heterogeneity at rest and during exercise. Also, the relationship between local skeletal muscle FFA uptake and perfusion was studied. Nine young adult male monozygotic twin pairs with significant difference in physical activity [229 min (SD 156) average time spent for conditioning exercise per week in more and 98 min (SD 71) in less active twins, P = 0.013] and aerobic fitness [18% (SD 10) difference in maximum O2 uptake] between brothers were studied using positron emission tomography. Submaximal knee-extension exercise increased perfusion, FFA uptake, and oxygen uptake in quadriceps femoris muscles 6-10 times compared with resting values (P < 0.001). More active twins tended to utilize more oxygen, while no differences were found in muscle perfusion or FFA uptake between groups. Mean perfusion and FFA uptake correlated strongly at a whole muscle level, both at rest (r = 0.97, P = 0.03 in more and r = 0.98, P = 0.02 in less active twins) and during exercise (r = 0.99, P = 0.01 and r = 0.94, P = 0.06), but at the voxel level (87 mm3) correlation was only moderate during exercise [r = 0.73 (SD 0.08) vs. r = 0.74 (SD 0.10), P = 0.92] and weak at rest [r = 0.28 (SD 0.13) vs. r = 0.33 (SD 0.21), P = 0.58]. Exercise decreased both perfusion and FFA uptake heterogeneity within the muscles (P < 0.001) similarly in both groups. In conclusion, long-term history of moderately increased physical activity tends to enhance muscle oxidative metabolism, but it does not have any significant influence on the FFA uptake or perfusion rates or their heterogeneity in skeletal muscle. Submaximal knee-extension exercise decreases heterogeneity of muscle FFA uptake and perfusion and improves matching between local muscle perfusion and FFA uptake. Thus it seems that the genetic influence is more important to determine the heterogeneity of perfusion and FFA uptake in skeletal muscle than exercise training.

Blood Flow Velocity↗

Genetic and environmental contribution to postural balance of older women in single and dual task situations.

The purpose of the present study was to examine the effect of a second task on postural balance and to determine the role of genetic influences on postural balance when dual tasking among 206 monozygotic and 227 dizygotic female twins, aged 63-76 years. Balance was measured as medio-lateral and antero-posterior velocity of the centre of pressure (COP) (mm/s) and velocity moment (mm(2)/s) while standing on a force platform. Doing an arithmetic task increased movement of the COP while the hand motor task had no effect on movement of the COP. The genetic contribution to balance in the single task situation was minor (14%, 95% confidence interval, CI: 11-35%) whereas in the dual task situation it was moderate (28%, 95% CI: 0.02-42%). The finding can be explained in the light of the underlying phenotypes of dual tasking, such as cognitive processing that is found to be under considerable genetically controlled even in old age. Moreover, the present study supports previous studies suggesting that, especially among older people, when simultaneously maintaining balance and performing another cognitively demanding task, additional central processing is recruited.

Aged↗

Acquired obesity increases CD68 and tumor necrosis factor-alpha and decreases adiponectin gene expression in adipose tissue: a study in monozygotic twins.

CONTEXT: Both acquired and genetic factors regulate adipose tissue function. OBJECTIVE: We determined whether adipose tissue mRNA expression is regulated by obesity, independently of genetic effects, by studying monozygotic (MZ) twins. DESIGN: Seventeen healthy pairs of MZ twins aged 24-27 yr (body mass index 20.0-33.9 kg/m(2), intrapair differences in body weight 0.1-24.7 kg), were identified from the population-based FinnTwin16 cohort. Body fat percent was determined by dual-energy x-ray absorptiometry, sc and intraabdominal fat by magnetic resonance imaging, liver fat by proton spectroscopy, and insulin sensitivity by using the euglycemic insulin clamp technique. Adipocyte cell size and expression of 10 genes (real-time PCR) were determined in sc adipose tissue biopsies. Serum levels of some of the genes were measured using ELISA. RESULTS: Within MZ twin pairs, acquired obesity was significantly related to increased adipocyte size and increased adipose tissue mRNA expressions of leptin, TNFalpha and the macrophage marker CD68, and decreased mRNA expressions of adiponectin and peroxisome proliferator-activated receptor-gamma. Intrapair differences in liver fat correlated directly with those in leptin and CD68 expression. CD68 expression and serum TNFalpha concentrations were correlated with insulin resistance. CONCLUSIONS: Acquired obesity independent of genetic influences is able to increase expression of macrophage and inflammatory markers and decrease adiponectin expression in adipose tissue.

Absorptiometry, Photon↗

Genetic and environmental influences on stages of alcohol use across adolescence and into young adulthood.

The progression to alcohol dependence unfolds across multiple stages, including the decision to initiate use, the development of regular patterns of use, and (for some individuals) the subsequent development of problems associated with alcohol use. Using data from two population-based, longitudinal twin studies, FinnTwin16 (FT16) and FinnTwin12 (FT12), we applied multiple stage genetic models (Heath et al., Twin Res. 5 (2002) 113) to better understand the extent to which genetic and environmental influences impact the initiation of alcohol use, frequency of use in adolescence and young adulthood, and alcohol problems in young adulthood. Shared environmental factors played a large role in initiation, and a more moderate role on frequency of use, and it was largely the same influences acting across these stages of use. However, there was no significant evidence of shared environmental influences on alcohol problems in early adulthood. Problems were largely influenced by genetic factors that overlapped with genetic influences on frequency of use. Unique environmental factors were largely specific to each stage, with some overlap between alcohol problems and frequency of use at age 25.

Adolescent↗

Muscle dissatisfaction in young adult men.

BACKGROUND: Appearance concerns are of increasing importance in young men's lives. We investigated whether muscle dissatisfaction is associated with psychological symptoms, dietary supplement or anabolic steroid use, or physical activity in young men. METHODS: As a part of a questionnaire assessment of health-related behaviors in the population-based FinnTwin16 study, we assessed factors associated with muscle dissatisfaction in 1245 men aged 22-27 using logistic regression models. RESULTS: Of men, 30% experienced high muscle dissatisfaction, while 12% used supplements/steroids. Of highly muscle-dissatisfied men, 21.5% used supplements/steroids. Mean body mass index, waist circumference, or leisure aerobic activity index did not differ between individuals with high/low muscle dissatisfaction. Muscle dissatisfaction was significantly associated with a psychological and psychosomatic problems, alcohol and drug use, lower height satisfaction, sedentary lifestyle, poor subjective physical fitness, and lower life satisfaction. CONCLUSION: Muscle dissatisfaction and supplement/steroid use are relatively common, and are associated with psychological distress and markers of sedentary lifestyle.

Journal Article↗

Determinants of the progression in lumbar degeneration: a 5-year follow-up study of adult male monozygotic twins.

STUDY DESIGN: A 5-year follow-up study of exposure of discordant monozygotic twin pairs with repeated interviews and spine imaging. OBJECTIVE: The primary goals were to record changes in the degenerative signs over a 5-year interval and to estimate the effects of familial influences and suspected environmental risk factors on the speed of lumbar degeneration. SUMMARY OF BACKGROUND DATA: Traditionally, disc degeneration has been attributed to aging and environmental exposures; recently, a dominant effect of genetics has been revealed. Yet the etiopathogenesis of disc degeneration remains poorly understood and controversial despite being a primary target of diagnostic and therapeutic interventions. METHODS: Among 116 monozygotic twin pairs, which had been examined 5 years earlier, 75 pairs (150 men) were reexamined. They were imaged using the same MRI scanner and examination protocol as at baseline. The data were analyzed using statistical methods for longitudinal studies. RESULTS: Progression in disc height narrowing, disc bulging, osteophytosis, and fatty degeneration in the lumbar spine was seen in about 7% to 13% of the discs in 7% to 46% of subjects during 5-year follow-up. Few degenerative findings appear to reverse; few disc height measures increased, some anular tears were no longer visible, and bulging/herniation diminished. New anular tears (in axial view) were detected in 1.5%, disappeared in 2%, and were unchanged in 5.3% of discs; in the sagittal view, new high intensity zones findings were identified in 0.5%, were no longer apparent in 1.6%, and were unchanged in 7.1% of discs. There were no clear changes in upper endplates: in 2.1% of discs, the irregularity score increased and in 1.8% it decreased. Familial aggregation, reflecting genetic, and shared environmental influences, explained 47% to 66% of the variance in progression of degenerative signs on lumbar MRI, and resistance training and occupational physical loading together explained 2% to 10% of the progression in the degenerative signs in lumbar MRIs. CONCLUSIONS: Progression of disc height narrowing, bulging, osteophytes, and fatty degeneration was detected in about 10% or less of the T12-S1 discs. Development and disappearance of anular lesions were rarer. No clear changes were seen in endplate irregularities. The results also confirm that hereditary effects have a dominant role in the progression of disc degeneration and suggest that occupational lifting and leisure time resistance training have modest additional effects.

Adult↗

Gene expression profiles in Finnish twins with multiple sclerosis.

BACKGROUND: Since genetic alterations influencing susceptibility to multiple sclerosis (MS), the most common autoimmune demyelinating disease of the central nervous system (CNS), are as yet poorly understood, the purpose of this study was to identify genes responsible for MS by studying monozygotic (MZ) twin pairs discordant for MS. METHODS: In order to identify genes involved in MS development, the gene expression profiles in blood mononuclear cells obtained from eight MZ twin pairs discordant for MS were analyzed by cDNA microarray technology detecting the expression of 8 300 genes. The twins were collected from the Finnish Twin Cohort Study and both affected subjects and their healthy siblings underwent neurological evaluation and cerebral and spinal magnetic resonance imaging. Gene expressions were confirmed by relative quantitative reverse transcription PCR. RESULTS: It appeared that 25 genes were at least two-fold up-regulated and 15 genes down-regulated in 25% (2/8) of twins with MS when compared to their healthy siblings. Moreover, 6/25 genes were up-regulated in 40% of MS twins and one gene, interferon alpha-inducible protein (clone IFI-6-16) (G1P3), in 50% of them. The six most constantly expressed genes are (1) G1P3, (2) POU domain, class 3, transcription factor 1, (3) myxovirus resistance 2, (4) lysosomal-associated multispanning membrane protein-5, (5) hemoglobin alpha 2 and (6) hemoglobin beta. CONCLUSION: Over two-fold up-regulation of these six genes in almost half of MZ twins with MS suggests their role in MS pathogenesis. Studies using MZ MS twins obtained from genetically homogeneous population offer a unique opportunity to explore the genetic nature of MS.

Diseases in Twins↗

Association between height and coronary heart disease mortality: a prospective study of 35,000 twin pairs.

An inverse association between height and risk of coronary heart disease (CHD) is well demonstrated, but it is not known whether this association is because of genetic factors, socioeconomic background, or other environmental factors. Four population-based twin cohorts with register-based follow-up data on CHD mortality from Denmark (1966-1996), Finland (1975-2001), and Sweden (1963-2001 and 1972-2001) were used to investigate this question; response rates varied between 65% and 86%. Together, the cohorts included 74,704 twin individuals (35,042 complete twin pairs) with 5,943 CHD deaths during 1.99 million person-years of follow-up. Cox and conditional logistic regression models were used. Per 1-standard deviation decrease in height, height was inversely associated with CHD mortality in men (hazard ratio = 1.08, 95% confidence interval (CI): 1.04, 1.12) and in women (hazard ratio = 1.06, 95% CI: 1.01, 1.10). A twin who had died from CHD was on average shorter than the co-twin within monozygotic pairs (odds ratio = 1.27, 95% CI: 1.12, 1.44, with no sex difference), whereas a weaker association was found within dizygotic pairs in men (odds ratio = 1.01, 95% CI: 0.91, 1.13) and in women (odds ratio = 1.14, 95% CI: 1.01, 1.28). The inverse association between height and CHD mortality found within monozygotic discordant twin pairs suggests that this association is because of environmental factors that directly affect height and CHD risk.

Body Height↗