The University of Minnesota has played an important role in the resurgence and eventual mainstreaming of human behavioral genetics in psychology and psychiatry. We describe this history in the context of three major movements in behavioral genetics: (1) radical eugenics in the early 20th century, (2) resurgence of human behavioral genetics in the 1960s, largely using twin and adoption designs to obtain more precise estimates of genetic and environmental influences on individual differences in behavior; and (3) use of measured genotypes to understand behavior. University of Minnesota scientists made significant contributions especially in (2) and (3) in the domains of cognitive ability, drug abuse and mental health, and endophenotypes. These contributions are illustrated through a historical perspective of major figures and events in behavioral genetics.

It is widely recognized that dizygotic twinning (DZT) runs in families, but estimates of heritability from twin and family data are remarkably scarce and vary considerably. Here, we traced seven large, sometimes historical, multigeneration pedigrees from West Africans, fin de siècle French Jews, Canadians (two pedigrees), and the French royal family, in which twin births were recorded. We estimated heritability of twinning (of all types) as zygosity information was not available, diluting the true DZT heritability by a third or so. The estimates in the range 8−20% are remarkably consistent across time (8−19 generations) and ethnicities and also consistent with twin and family estimates.

Erikson asked what makes some people care for the future of the species and others not, calling this ‘generativity vs. stagnation’. In three studies, we addressed structure of this trait and its heritability. Study 1 (N = 1570), using structural models of the Loyola Generativity Scale , revealed three correlated factors consisting of (1) Establishing and aiding the next generation; (2) Maintaining the world; and (3) Symbolic immortality through a positive legacy. Study 2 (N = 311) successfully replicated this structure in an independent UK sample. Study 3 tested genetic and environmental influences on generativity. All three factors showed significant and substantial heritable influence. A general factor was required, which was also heritable. In resolving previous uncertainty over the transmission of generativity across generations, shared environmental transmission models fit poorly. Substantial unique environmental effects suggest strong cultural impacts on concern for the species. Generativity researchers may usefully adopt this three-factor scoring system, allowing research on the predictive power of each component of generativity as well as molecular genetic or biological studies.

DNA methylation-based age acceleration (DNAmAA) is associated with cancer, with both cancer tissue and blood showing increased DNAmAA. We aimed to investigate whether DNAmAA is associated with cancer risk within twin pairs discordant for cancer, and whether DNAmAA has the potential to serve as a biomarker for such. The study included 47 monozygotic and 48 same-sex-dizygotic cancer-discordant twin pairs from the Finnish Twin Cohort study with blood samples available between 17 and 31 years after the cancer diagnosis. We studied all cancers (95 pairs), then separately breast cancer (24 pairs) and all sites other than breast cancer (71 pairs). DNAmAA was calculated for seven models: Horvath, Horvath intrinsic epigenetic age acceleration, Hannum, Hannum intrinsic epigenetic age acceleration, Hannum extrinsic epigenetic age acceleration, PhenoAge and GrimAge. Within-pair differences in DNAmAA were analyzed by paired t tests and linear regression. Twin pairs sampled before cancer diagnosis did not differ significantly in DNAmAA. However, the within-pair differences in DNAmAA before cancer diagnosis increased significantly the closer the cancer diagnosis was, and this acceleration extended for years after the diagnosis. Pairs sampled after the diagnosis differed for DNAmAA with the Horvath models capturing cancer diagnosis-associated DNAmAA across all three cancer groupings. The results suggest that DNAmAA in blood is associated with cancer diagnosis. This may be due to epigenetic alterations in relation to cancer, its treatment or associated lifestyle changes. Based on the current study, the biomarker potential of DNAmAA in blood appears to be limited.

Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants’ biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants’ serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants’ fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality.

In this prospective study of mental health, we examine the influence of three interrelated traits — perceived stress, rumination, and daytime sleepiness — and their association with symptoms of anxiety and depression in early adolescence. Given the known associations between these traits, an important objective is to determine the extent to which they may independently predict anxiety/depression symptoms. Twin pairs from the Queensland Twin Adolescent Brain (QTAB) project were assessed on two occasions (N = 211 pairs aged 9−14 years at baseline and 152 pairs aged 10−16 years at follow-up). Linear regression models and quantitative genetic modeling were used to analyze the data. Prospectively, perceived stress, rumination, and daytime sleepiness accounted for 8−11% of the variation in later anxiety/depression; familial influences contributed strongly to these associations. However, only perceived stress significantly predicted change in anxiety/depression, accounting for 3% of variance at follow-up after adjusting for anxiety/depression at baseline, although it did not do so independently of rumination and daytime sleepiness. Bidirectional effects were found between all traits over time. These findings suggest an underlying architecture that is shared, to some degree, by all traits, while the literature points to hypothalamic–pituitary–adrenal (HPA) axis and/or circadian systems as potential sources of overlapping influence and possible avenues for intervention.

Attention-deficit/hyperactivity disorder (ADHD) and obesity are positively associated, with increasing evidence that they share genetic risk factors. Our aim was to examine whether these findings apply to both types of ADHD symptoms for female and male adolescents. We used data from 791 girl and 735 boy twins ages 16−17 years to examine sex-specific phenotypic correlations between the presence of ADHD symptoms and overweight/obese status. For correlations exceeding .20, we then fit bivariate twin models to estimate the genetic and environmental correlations between the presence of ADHD symptoms and overweight/obese status. ADHD symptoms and height/weight were parent- and self-reported, respectively. Phenotypic correlations were .30 (girls) and .08 (boys) for inattention and overweight/obese status and .23 (girls) and .14 (boys) for hyperactivity/impulsivity and overweight/obese status. In girls, both types of ADHD symptoms and overweight/obese status were highly heritable, with unique environmental effects comprising the remaining variance. Furthermore, shared genetic effects explained most of the phenotypic correlations in girls. Results suggest that the positive association of both types of ADHD symptoms with obesity may be stronger in girls than boys. Further, in girls, these associations may stem primarily from shared genetic factors.

Colorectal cancer is the third most common and second most deadly type of cancer worldwide, with approximately 1.9 million cases and 0.9 million deaths worldwide in 2020. Previous studies have shown that estrogen and testosterone hormones are associated with colorectal cancer risk and mortality. However, the potential effect of their precursor, dehydroepiandrosterone sulfate (DHEAS), on colorectal cancer risk has not been investigated. Therefore, evaluating DHEAS’s effect on colorectal cancer will expand our understanding of the hormonal contribution to colorectal cancer risk. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effect of DHEAS on colorectal cancer. We obtained DHEAS and colorectal cancer genomewide association study (GWAS) summary statistics from the Leipzig Health Atlas and the GWAS catalog and conducted MR analyses using the TwoSampleMR R package. Our results suggest that higher DHEAS levels are causally associated with decreased colorectal cancer risk (odds ratio per unit increase in DHEAS levels z score = 0.70; 95% confidence interval [0.51, 0.96]), which is in line with previous observations in a case–control study of colon cancer. The outcome of this study will be beneficial in developing plasma DHEAS-based biomarkers in colorectal cancer. Further studies should be conducted to interpret the DHEAS-colorectal cancer association among different ancestries and populations.

It has been hypothesized that even ‘perfect’ polygenic scores (PGSs) composed of only causal variants may not be fully portable between different social groups owing to gene-by-environment interactions modifying the expression of relevant variants. The impacts of such interactions involving two forms of social adversity (low socioeconomic status [SES] and discrimination) are examined in relation to the expressivity of a PGS for educational attainment composed of putatively causal variants in a large, representatively sampled and genotyped cohort of US children. A relatively small-magnitude Scarr–Rowe effect is present (SES × PGSEDU predicting General Cognitive Ability [GCA]; sR = .02, 95% CI [.00, .04]), as is a distinct discrimination × PGSEDU interaction predicting GCA (sR = −.02, 95% CI [−.05, 00]). Both are independent of the confounding main effects of 10 ancestral principal components, PGSEDU, SES, discrimination and interactions among these factors. No sex differences were found. These interactions were examined in relation to phenotypic and genotypic data on height, a prospectively more socially neutral trait. They were absent in both cases. The discrimination × PGSEDU interaction is a co-moderator of the differences posited in modern versions of Spearman’s hypothesis (along with shared environmentality), lending support to certain environmental explanations of those differences. Behavior-genetic analysis of self-reported discrimination indicates that it is nonsignificantly heritable (h2 = .027, 95% CI [−.05, .10]), meaning that it is not merely proxying some underlying source of heritable phenotypic variability. This suggests that experiences of discrimination might stem instead from the action of purely social forces.

Living in the same household exposes family members to shared environments and may be reflected in estimates of shared environment in twin analyses. The age at the separation of cotwins in a twin pair marks the end of such shared exposure, and the age of separation is commonly self-reported in studies. The objective of the study was to summarize the age at separation from residential records and use it to validate with self-reported separation status and age at the third and fourth wave of data collection in the FinnTwin12 cohort. Age at separation was generated from the address information, linking it to the Finnish Population information system since birth. Descriptive statistics by sex and zygosity are presented. The mean age at separation from residential records was 20.36 years old. Women separated earlier than men and dizygotic pairs earlier than monozygotic pairs. We also calculated the sensitivity and specificity with the self-reported separation status at waves 3 and 4, and interrater reliability with the self-reported separation age at wave 4. Age at separation from residential records had a relatively poor agreement with the self-report. This work enables us to use a more precise and objective measure for the shared environment in future twin studies.

It is crucial to understand the genetic mechanisms and biological pathways underlying the relationship between obesity and serum lipid levels. Structural equation models (SEMs) were constructed to calculate heritability for body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and the genetic connections between BMI and the four classes of lipids using 1197 pairs of twins from the Chinese National Twin Registry (CNTR). Bivariate genomewide association studies (GWAS) were performed to identify genetic variants associated with BMI and lipids using the records of 457 individuals, and the results were further validated in 289 individuals. The genetic background affecting BMI may differ by gender, and the heritability of males and females was 71% (95% CI [.66, .75]) and 39% (95% CI [.15, .71]) respectively. BMI was positively correlated with TC, TG and LDL-C in phenotypic and genetic correlation, while negatively correlated with HDL-C. There were gender differences in the correlation between BMI and lipids. Bivariate GWAS analysis and validation stage found 7 genes (LOC105378740, LINC02506, CSMD1, MELK, FAM81A, ERAL1 and MIR144) that were possibly related to BMI and lipid levels. The significant biological pathways were the regulation of cholesterol reverse transport and the regulation of high-density lipoprotein particle clearance (p < .001). BMI and blood lipid levels were affected by genetic factors, and they were genetically correlated. There might be gender differences in their genetic correlation. Bivariate GWAS analysis found MIR144 gene and its related biological pathways may influence obesity and lipid levels.

The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%–72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%–77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%–16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).

Discordant monozygotic (MZ) twin methodologies are considered one of the foremost statistical approaches for estimating the influence of environmental factors on phenotypic variance. Limitations associated with the discordant MZ twin approach generates an inability to estimate particular relationships and adjust estimates for the confounding influence of gene-nonshared environment interactions. Recent advancements in molecular genetics, however, can provide the opportunity to address these limitations. The current study reviews an alternative technique, genetically adjusted propensity scores (GAPS) matching, that integrates observed genetic and environmental information to adjust for the confounding of these factors in nonkin individuals. Simulations and a real data example were used to compare the GAPS matching approach to the discordant MZ twin method. Although the results of the simulated comparisons demonstrated that the discordant MZ twin approach remains the more robust statistical technique to adjust for shared environmental and genetic factors, GAPS matching — under certain conditions — could represent a viable alternative when MZ twin samples are unavailable. Overall, the findings suggest that GAPS matching can potentially provide an alternative to the discordant MZ twin approach when limited variation exists between identical twin pairs. Moreover, the ability to adjust for gene-nonshared environment interactions represents a potential advancement associated with the GAPS approach. The limitations of the approach, as well as polygenic risk scores, are also discussed.

Mitochondrion regulates cellular metabolism with the aid of its respiratory complexes; any defect within these complexes can result in mitochondrial malfunction and various conditions. One such mutation can occur in SLC25A10, resulting in mitochondrial DNA depletion syndrome. It should be noted that the pattern of inheritance of this syndrome is autosomal recessive. However, we present a case with compound heterozygous mutations within this gene resulting in disease. An 18-year-old female was referred to our clinic due to menopause with a medical history of hearing loss, spasticity, hypotonia and quadriparesis. The child’s birth and development were uneventful until the initiation of movement reduction and hypotonia when she was 12 months old. Afterward, the hypotonia progressed to quadriparesis and spasticity throughout the years. Our patient became completely quadriplegic up to the age of 3 and became completely deaf at 10. Her puberty onset was at the age of 9, and no significant event took place until she was 17 years old when suddenly her periods, which were regular until that time, became irregular and ceased after a year; hence, a thorough evaluation began, but similar to her previous evaluations all tests were insignificant. Nonetheless, we suspected an underlying metabolic or genetic defect; thus, we ordered a whole-exome sequencing (WES) workup and found simultaneous heterozygous mutations within SLC25A10, HFE and TTN genes that could explain her condition. When all other tests fail, and we suspect an underlying genetic or metabolic cause, WES can be of great value.

Genes associated with educational attainment may be related to or interact with adolescent alcohol, tobacco and cannabis use. Potential gene–environment interplay between educational attainment polygenic scores (EA-PGS) and adolescent alcohol, tobacco, and cannabis use was evaluated with a series of regression models fitted to data from a sample of 1871 adult Australian twins. All models controlled for age, age2, cohort, sex and genetic ancestry as fixed effects, and a genetic relatedness matrix was included as a random effect. Although there was no evidence that adolescent alcohol, tobacco or cannabis use interacted with EA-PGS to influence educational attainment, there was a significant, positive gene–environment correlation with adolescent alcohol use at all PGS thresholds (ps <.02). Higher EA-PGS were associated with an increased likelihood of using alcohol as an adolescent (ΔR2 ranged from 0.5% to 1.1%). The positive gene–environment correlation suggests a complex relationship between educational attainment and alcohol use that is due to common genetic factors.

Heritability of age at menarche (AAM) in African populations remains largely unknown. A question on AAM was given to 1803 [454 monozygotic (MZ), 823 same-sex dizygotic (DZ), and 526 female members of opposite sex] adolescent twins attending public schools in Lagos State, Nigeria. The age range of the sample was 12–18 years, with a mean (SD) of 14.57 (±1.70) years. The data included 905 missing cases consisting of those who had not experienced menarche and did not recall AAM. Missing values were imputed using the Expectation-Maximization algorithm. Kaplan–Meier analysis based on the imputed data yielded 13.23 years [95% CI [13.18, 13.28] for the mean and 13.00 years [95% CI [12.96, 13.04] for the median of AAM. Twin correlation and model-fitting analyses were performed on the basis of those who reported AAM (MZ = 82 complete pairs and 38 cotwin missing cases; DZ = 157 complete pairs and 99 cotwin missing cases). Maximum likelihood MZ and DZ twin correlations for AAM were .63 (95% CI [.48, .74]) and .33 (95% CI [.19, .45]) respectively. Model-fitting analyses indicated that 58% (95% CI [46, 67]) of the variance of AAM was associated with additive genetic influences with the remaining variance, 42% (33−54) being due to nonshared environmental influences including measurement error. The heritability estimate found in this study was within the range of those found in Asian and Western twin samples.

This case reports peripheral blood mononuclear cell (PBMC) transcriptomic changes in a pair of male monozygotic pediatric twins with metabolic syndrome (MetS) undertaking assisted weight loss. These 14-year-old boys presented with similar baseline biochemistry and body composition. After a 16-week weight-loss intervention, percent body weight loss was similar (Twin A 12%, and Twin B 13%). MetS resolved in Twin A but Twin B maintained elevated triglycerides after weight loss. Analysis of the PBMC transcriptome before and after weight loss revealed very different changes in gene expression including differences in the direction of expression of genes related to immune cell activation. 48.7% of genes that were downregulated in Twin A were upregulated in Twin B. This case highlights a novel approach to report the influence of chronic low-grade inflammation and metabolic dysfunction on the PBMC transcriptome. It explores whether expression of genes related to immune functions may underlie the differences in response to weight loss or whether transcriptomic alterations in immune cells may precede more traditional biomarkers of chronic pro-inflammation. These monozygotic twins present an example of divergence of phenotypic outcomes despite identical genetic background and similar treatment response.

The relationship between pitch-naming ability and childhood onset of music training is well established and thought to reflect both genetic predisposition and music training during a critical period. However, the importance of the amount of practice during this period has not been investigated. In a population sample of twins (N = 1447, 39% male, 367 complete twin pairs) and a sample of 290 professional musicians (51% male), we investigated the role of genes, age of onset of playing music and accumulated childhood practice on pitch-naming ability. A significant correlation between pitch-naming scores for monozygotic (r = .27, p < .001) but not dizygotic twin pairs (r = −.04, p = .63) supported the role of genetic factors. In professional musicians, the amount of practice accumulated between ages 6 and 11 predicted pitch-naming accuracy (p = .025). In twins, age of onset was no longer a significant predictor once practice was considered. Combined, these findings are in line with the notion that pitch-naming ability is associated with both genetic factors and amount of early practice, rather than just age of onset per se. This may reflect a dose–response relation between practice and pitch-naming ability in genetically predisposed individuals. Alternatively, children who excel at pitch-naming may have an increased tendency to practice.

The role of superficial anastomoses in the survival of fetuses with twin-twin transfusion syndrome after fetoscopic laser photocoagulation is unknown. This study aimed to evaluate how superficial anastomoses affect the circulatory dynamics of both fetuses with twin-twin transfusion syndrome using ductus venous Doppler waveforms. We included all twin-twin transfusion syndrome (TTTS) patients who underwent fetoscopic laser photocoagulation in our institution from 2006 to 2019; fetal demise cases after fetoscopic laser photocoagulation were excluded. We recorded ductus venous Doppler waveforms on the same day or one day before fetoscopic laser photocoagulation and one day after fetoscopic laser photocoagulation and measured the ductus venous pulsatility index and velocity ratios. We compared these z-scores of donor and recipient twins between a group without superficial anastomoses and the groups with arterio-arterial or veno-venous anastomoses. A total of 115 surviving TTTS placentas after fetoscopic laser photocoagulation were analyzed. The ductus venous pulsatility index and all ratios were better in recipient twins with arterio-arterial anastomoses than in those without. The a-wave-related ratios were better in recipient twins with veno-venous anastomoses than in those without. Superficial anastomoses reduced the blood volume and arterio-arterial anastomoses protected the diastolic cardiac function in recipient twin-twin transfusion syndrome twins before fetoscopic laser photocoagulation. Superficial anastomoses in TTTS equilibrate blood pressure between donor and recipient twins.

Transcriptional changes involved in neuronal recovery after sports-related concussion (SRC) may be obscured by inter-individual variation in mRNA expression and nonspecific changes related to physical exertion. Using a co-twin study, the objective of this study was to identify important differences in mRNA expression among a single pair of monozygotic (MZ) twins discordant for concussion. A pair of MZ twins were enrolled as part of a larger study of concussion biomarkers among collegiate athletes. During the study, Twin A sustained SRC, allowing comparison of mRNA expression to the nonconcussed Twin B. Twin A clinically recovered by Day 7. mRNA expression was measured pre-injury and at 6 h and 7 days postinjury using Affymetrix HG-U133 Plus 2.0 microarray. Changes in mRNA expression from pre-injury to each postinjury time point were compared between the twins; differences >1.5-fold were considered important. Kyoto Encyclopedia of Genes and Genomes identified biologic networks associated with important transcripts. Among 38,000 analyzed genes, important changes were identified in 153 genes. The ErbB (epidermal growth factor receptor) signaling pathway was identified as the top transcriptional network from pre-injury to 7 days postinjury. Genes in this pathway with important transcriptional changes included epidermal growth factor (2.41), epiregulin (1.73), neuregulin 1 (1.54) and mechanistic target of rapamycin (1.51). In conclusion, the ErbB signaling pathway was identified as a potential regulator of clinical recovery in a MZ twin pair discordant for SRC. A co-twin study design may be a useful method for identifying important gene pathways associated with concussion recovery.