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European Heart Journal Feb 2023Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been...
AIMS
Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association.
METHODS AND RESULTS
Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD-dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27-1.58) for 1 CMD and 2.10 (1.73-2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD-dementia association was attenuated among monozygotic [0.99 (0.50-1.98)] but not dizygotic [1.55 (1.15-2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia.
CONCLUSION
Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.
Topics: Humans; Cohort Studies; Multimorbidity; Sweden; Diseases in Twins; Risk Factors; Stroke; Registries
PubMed: 36577740
DOI: 10.1093/eurheartj/ehac744 -
Medicina (Kaunas, Lithuania) Nov 2022: Subcortical grey matter structures play essential roles in cognitive, affective, social, and motoric functions in humans. Their volume changes with age, and decreased...
: Subcortical grey matter structures play essential roles in cognitive, affective, social, and motoric functions in humans. Their volume changes with age, and decreased volumes have been linked with many neuropsychiatric disorders. The aim of our study was to examine the heritability of six subcortical brain volumes (the amygdala, caudate nucleus, pallidum, putamen, thalamus, and nucleus accumbens) and four general brain volumes (the total intra-cranial volume and the grey matter, white matter, and cerebrospinal fluid (CSF) volume) in twins. : A total of 118 healthy adult twins from the Hungarian Twin Registry (86 monozygotic and 32 dizygotic; median age 50 ± 27 years) underwent brain magnetic resonance imaging. Two automated volumetry pipelines, Computational Anatomy Toolbox 12 (CAT12) and volBrain, were used to calculate the subcortical and general brain volumes from three-dimensional T1-weighted images. Age- and sex-adjusted monozygotic and dizygotic intra-pair correlations were calculated, and the univariate ACE model was applied. Pearson's correlation test was used to compare the results obtained by the two pipelines. : The age- and sex-adjusted heritability estimates, using CAT12 for the amygdala, caudate nucleus, pallidum, putamen, and nucleus accumbens, were between 0.75 and 0.95. The thalamus volume was more strongly influenced by common environmental factors (C = 0.45-0.73). The heritability estimates, using volBrain, were between 0.69 and 0.92 for the nucleus accumbens, pallidum, putamen, right amygdala, and caudate nucleus. The left amygdala and thalamus were more strongly influenced by common environmental factors (C = 0.72-0.85). A strong correlation between CAT12 and volBrain (r = 0.74-0.94) was obtained for all volumes. : The majority of examined subcortical volumes appeared to be strongly heritable. The thalamus was more strongly influenced by common environmental factors when investigated with both segmentation methods. Our results underline the importance of identifying the relevant genes responsible for variations in the subcortical structure volume and associated diseases.
Topics: Adult; Aged; Humans; Middle Aged; Young Adult; Brain; Gray Matter; Magnetic Resonance Imaging; Twins
PubMed: 36422226
DOI: 10.3390/medicina58111687 -
Animals : An Open Access Journal From... Feb 2021Twinning in Holstein dairy cows has increased over time concurrent with increased milk production. Twinning in dairy cattle is not desirable due to the negative effects... (Review)
Review
Twinning in Holstein dairy cows has increased over time concurrent with increased milk production. Twinning in dairy cattle is not desirable due to the negative effects on both cows that calve twins and calves born as twins that result in economic losses to dairy farms. Although a twin pregnancy could bring additional income from extra calves and shorten gestation length, twinning compromises milk production, increases the incidence of dystocia and perinatal mortality, decreases calf birth weight, increases the incidence of metabolic diseases, decreases fertility, increases the incidence of freemartinism, increases overall culling risks, and shortens the productive lifespan of cows. Based on a summary of economic analyses from several studies, the estimated losses due to twinning range between $59 to $161 per twin pregnancy. Most twinning in dairy cows is dizygotic and directly related to the incidence of double ovulations, and economic losses are greater for unilateral than for bilateral twins. Hormonal manipulation before artificial insemination that allows for timed artificial insemination is a primary strategy for decreasing twinning in dairy cows before it occurs by decreasing the incidence of double ovulation thereby decreasing conception of dizygotic twins and the associated negative economic consequences. When twins are diagnosed early during gestation, management options might include doing nothing, terminating the pregnancy, or attempting manual embryo reduction. Based on a recent economic analysis of these options, attempting manual embryo reduction decreased the economic losses of a twin pregnancy by $23 to $45.
PubMed: 33672462
DOI: 10.3390/ani11020552 -
European Journal of Medical Genetics Sep 2020The term chimera has been borrowed from Greek mythology and has a long history of use in biology and genetics. A chimera is an organism whose cells are derived from two... (Review)
Review
The term chimera has been borrowed from Greek mythology and has a long history of use in biology and genetics. A chimera is an organism whose cells are derived from two or more zygotes. Recipients of tissue and organ transplants are artificial chimeras. This review concerns natural human chimeras. The first human chimera was reported in 1953. Natural chimeras can arise in various ways. Fetal and maternal cells can cross the placental barrier so that both mother and child may become microchimeras. Two zygotes can fuse together during an early embryonic stage to form a fusion chimera. Most chimeras remain undetected, especially if both zygotes are of the same genetic sex. Many are discovered accidently, for example, during a routine blood group test. Even sex-discordant chimeras can have a normal male or female phenotype. Only 28 of the 50 individuals with a 46,XX/46,XY karyotype were either true hermaphrodites or had ambiguous genitalia. Blood chimeras are formed by blood transfusion between dizygotic twins via the shared placenta and are more common than was once assumed. In marmoset monkey twins the exchange via the placenta is not limited to blood but can involve other tissues, including germ cells. To date there are no examples in humans of twin chimeras involving germ cells. If human chimeras are more common than hitherto thought there could be many medical, social, forensic, and legal implications. More multidisciplinary research is required for a better understanding of this fascinating subject.
Topics: Chromosome Disorders; Disorders of Sex Development; Humans; Karyotype; Mosaicism; Phenotype
PubMed: 32565253
DOI: 10.1016/j.ejmg.2020.103971 -
Scientific Reports Jul 2022Individual differences in behaviour, traits and mental-health are partially heritable. Traditionally, studies have focused on quantifying the heritability of high-order...
Individual differences in behaviour, traits and mental-health are partially heritable. Traditionally, studies have focused on quantifying the heritability of high-order characteristics, such as happiness or education attainment. Here, we quantify the degree of heritability of lower-level mental processes that likely contribute to complex traits and behaviour. In particular, we quantify the degree of heritability of cognitive and affective factors that contribute to the generation of beliefs about risk, which drive behavior in domains ranging from finance to health. Monozygotic and dizygotic twin pairs completed a belief formation task. We first show that beliefs about risk are associated with vividness of imagination, affective evaluation and learning abilities. We then demonstrate that the genetic contribution to individual differences in these processes range between 13.5 and 39%, with affect evaluation showing a particular robust heritability component. These results provide clues to which mental factors may be driving the heritability component of beliefs formation, which in turn contribute to the heritability of complex traits.
Topics: Educational Status; Humans; Multifactorial Inheritance; Phenotype; Twins, Dizygotic
PubMed: 35821231
DOI: 10.1038/s41598-022-15492-0 -
EFORT Open Reviews May 2022Idiopathic scoliosis is the most common spinal deformity and affects 1-3% of children and adolescents. Idiopathic scoliosis may run in families and the purpose of this... (Review)
Review
PURPOSE
Idiopathic scoliosis is the most common spinal deformity and affects 1-3% of children and adolescents. Idiopathic scoliosis may run in families and the purpose of this systematic review was to describe the degree of heritability.
METHODS
We searched Medline, Web of Science and EMBASE for family and twin studies reporting heritability estimates for idiopathic scoliosis, or studies from which heritability estimates could be calculated. Reference lists were screened for additional papers. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol was registered at PROSPERO (registration number: CRD42022307329).
RESULTS
The literature search identified 1134 reports. After full-text screening, nine eligible reports were included for data extraction. Seven were twin studies containing between 5 and 526 pairs, and two were family studies with 1149 and 2732 individuals, respectively. Quality was 'good' in four studies and 'fair' in five studies. In general, studies with radiograph-confirmed diagnosis reported higher heritability estimates than studies with self-reported diagnosis. Population-based twin studies reported lower heritability estimates than clinic-based twin studies. Family-based studies reported higher heritability estimates than twin studies. Pairwise concordance for scoliosis ranged from 0.11 to 1.00 in monozygotic twins and from 0 to 1.0 in dizygotic twins. A meta-analysis of three studies resulted in a narrow sense heritability estimate of 0.57 (95% CI: 0.29-0.86).
CONCLUSION
Twin and family studies indicate a hereditary component in idiopathic scoliosis, but study heterogeneity is large, and the degree of the heritability is uncertain. Nevertheless, known genetic variants associated with idiopathic scoliosis can still only explain a minor part of heritability.
PubMed: 35638601
DOI: 10.1530/EOR-22-0026 -
Biological Psychiatry Mar 2024Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from...
BACKGROUND
Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD.
METHODS
We examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.
RESULTS
Sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62-4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05-0.08] and b = 0.09 [95% CI 0.08-0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08-1.23]).
CONCLUSIONS
Our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Depressive Disorder, Major; Genome-Wide Association Study; Prospective Studies; Risk Factors; Mendelian Randomization Analysis
PubMed: 37562520
DOI: 10.1016/j.biopsych.2023.07.017 -
Nature Mar 2022Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental...
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.
Topics: Genetic Predisposition to Disease; Humans; Interleukin-2; Multiple Sclerosis; OX40 Ligand; Twins, Dizygotic; Twins, Monozygotic
PubMed: 35173329
DOI: 10.1038/s41586-022-04419-4 -
Developmental Neuroscience 2021Autism spectrum disorders (ASD) comprise a group of heterogeneous neurodevelopmental conditions characterized by impaired social interactions and repetitive behaviors... (Review)
Review
Autism spectrum disorders (ASD) comprise a group of heterogeneous neurodevelopmental conditions characterized by impaired social interactions and repetitive behaviors with symptom onset in early infancy. The genetic risks for ASD have long been appreciated: concordance of ASD diagnosis may be as high as 90% for monozygotic twins and 30% for dizygotic twins, and hundreds of mutations in single genes have been associated with ASD. Nevertheless, only 5-30% of ASD cases can be explained by a known genetic cause, suggesting that genetics is not the only factor at play. More recently, several studies reported that up to 40% of infants with cerebellar hemorrhages and lesions are diagnosed with ASD. These hemorrhages are overrepresented in severely premature infants, who are born during a period of highly dynamic cerebellar development that encompasses an approximately 5-fold size expansion, an increase in structural complexity, and remarkable rearrangements of local neural circuits. The incidence of ASD-causing cerebellar hemorrhages during this window supports the hypothesis that abnormal cerebellar development may be a primary risk factor for ASD. However, the links between developmental deficits in the cerebellum and the neurological dysfunctions underlying ASD are not completely understood. Here, we discuss key processes in cerebellar development, what happens to the cerebellar circuit when development is interrupted, and how impaired cerebellar function leads to social and cognitive impairments. We explore a central question: Is cerebellar development important for the generation of the social and cognitive brain or is the cerebellum part of the social and cognitive brain itself?
Topics: Autism Spectrum Disorder; Brain; Cerebellum; Humans; Infant
PubMed: 33823515
DOI: 10.1159/000515189 -
Human Reproduction (Oxford, England) Jan 2024Spontaneous dizygotic (DZ) twins, i.e. twins conceived without the use of ARTs, run in families and their prevalence varies widely around the globe. In contrast,... (Meta-Analysis)
Meta-Analysis
Spontaneous dizygotic (DZ) twins, i.e. twins conceived without the use of ARTs, run in families and their prevalence varies widely around the globe. In contrast, monozygotic (MZ) twins occur at a constant rate across time and geographical regions and, with some rare exceptions, do not cluster in families. The leading hypothesis for MZ twins, which arise when a zygote splits during preimplantation stages of development, is random occurrence. We have found the first series of genes underlying the liability of being the mother of DZ twins and have shown that being an MZ twin is strongly associated with a stable DNA methylation signature in child and adult somatic tissues. Because identical twins keep this molecular signature across the lifespan, this discovery opens up completely new possibilities for the retrospective diagnosis of whether a person is an MZ twin whose co-twin may have vanished in the early stages of pregnancy. Here, we summarize the gene finding results for mothers of DZ twins based on genetic association studies followed by meta-analysis, and further present the striking epigenetic results for MZ twins.
Topics: Female; Humans; Pregnancy; Fertilization; Genetic Association Studies; Retrospective Studies; Twins, Dizygotic; Twins, Monozygotic; Infant, Newborn
PubMed: 38052159
DOI: 10.1093/humrep/dead131