Clinical utility of pharmacogenetics in a psychiatric and primary care population.

This study evaluated the timing, use, and clinical outcomes of the GeneFolio® Pharmacogenomic Panel in a healthcare setting with patients managed by primary care providers or by psychiatrists. Participants were randomized to receive a pharmacogenetics report at four weeks or 12 weeks. After DNA collection and genetic analysis, pharmacists produced a recommendation report which was given to providers at the randomization week. The four-week group decreased depression severity (PHQ-9 and BDI) faster than the 12-week group (p = 0.0196), and psychiatrists' patients decreased their depression severity faster than primary care patients (PHQ-9 p = 0.0005, BDI p = 0.0218). Mean mental quality of life increased over time (p < 0.0001), but it increased slower for patients taking drugs in the Significant drug-drug-gene interaction category (p = 0.0012). Mental quality of life, depression severity, and clinical outcomes were improved by GeneFolio® pharmacogenomic testing regardless of provider type, with earlier testing improving outcomes sooner.

Insights into the Antibacterial Mechanism of Action of Chelating Agents by Selective Deprivation of Iron, Manganese, and Zinc.

Bacterial growth and proliferation can be restricted by limiting the availability of metal ions in their environment. Humans sequester iron, manganese, and zinc to help prevent infection by pathogens, a system termed nutritional immunity. Commercially used chelants have high binding affinities with a variety of metal ions, which may lead to antibacterial properties that mimic these innate immune processes. However, the modes of action of many of these chelating agents in bacterial growth inhibition and their selectivity in metal deprivation in cellulo remain ill-defined. We address this shortcoming by examining the effect of 11 chelators on Escherichia coli growth and their impact on the cellular concentration of five metals. The following four distinct effects were uncovered: (i) no apparent alteration in metal composition, (ii) depletion of manganese alongside reductions in iron and zinc levels, (iii) reduced zinc levels with a modest reduction in manganese, and (iv) reduced iron levels coupled with elevated manganese. These effects do not correlate with the absolute known chelant metal ion affinities in solution; however, for at least five chelators for which key data are available, they can be explained by differences in the relative affinity of chelants for each metal ion. The results reveal significant insights into the mechanism of growth inhibition by chelants, highlighting their potential as antibacterials and as tools to probe how bacteria tolerate selective metal deprivation. IMPORTANCE Chelating agents are widely used in industry and consumer goods to control metal availability, with bacterial growth restriction as a secondary benefit for preservation. However, the antibacterial mechanism of action of chelants is largely unknown, particularly with respect to the impact on cellular metal concentrations. The work presented here uncovers distinct metal starvation effects imposed by different chelants on the model Gram-negative bacterium Escherichia coli. The chelators were studied both individually and in pairs, with the majority producing synergistic effects in combinations that maximize antibacterial hostility. The judicious selection of chelants based on contrasting cellular effects should enable reductions in the quantities of chelant required in numerous commercial products and presents opportunities to replace problematic chemistries with biodegradable alternatives.

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Intergenerational Transmission of Education and ADHD: Effects of Parental Genotypes.

It remains a challenge to determine whether children resemble their parents due to nature, nurture, or a mixture of both. Here we used a design that exploits the distinction between transmitted and non-transmitted alleles in genetic transmission from parent to offspring. Two separate polygenic scores (PGS) were calculated on the basis of the transmitted and non-transmitted alleles. The effect of the non-transmitted PGS is necessarily mediated by parental phenotypes, insofar as they contribute to the rearing environment of the offspring (genetic nurturing). We calculated transmitted and non-transmitted PGSs associated with adult educational attainment (EA) and PGSs associated with childhood ADHD in a general population sample of trios, i.e. child or adult offspring and their parents (N = 1120-2518). We tested if the EA and ADHD (non-)transmitted PGSs were associated with childhood academic achievement and ADHD in offspring. Based on the earlier findings for shared environment, we hypothesized to find genetic nurturing for academic achievement, but not for ADHD. In adults, both transmitted (R2 = 7.6%) and non-transmitted (R2 = 1.7%) EA PGSs were associated with offspring EA, evidencing genetic nurturing. In children around age 12, academic achievement was associated with the transmitted EA PGSs (R2 = 5.7%), but we found no support for genetic nurturing (R2 ~ 0.1%). The ADHD PGSs were not significantly associated with academic achievement (R2 ~ 0.6%). ADHD symptoms in children were only associated with transmitted EA PGSs and ADHD PGSs (R2 = 1-2%). Based on these results, we conclude that the associations between parent characteristics and offspring outcomes in childhood are mainly to be attributable to the effects of genes that are shared by parents and children.

Chimerism in health and potential implications on behavior: A systematic review.

In this review, we focus on the phenomenon of chimerism and especially microchimerism as one of the currently underexplored explanations for differences in health and behavior. Chimerism is an amalgamation of cells from two or more unique zygotes within a single organism, with microchimerism defined by a minor cell population of <1%. This article first presents an overview of the primary techniques employed to detect and quantify the presence of microchimerism and then reviews empirical studies of chimerism in mammals including primates and humans. In women, male microchimerism, a condition suggested to be the result of fetomaternal exchange in utero, is relatively easily detected by polymerase chain reaction molecular techniques targeting Y-chromosomal markers. Consequently, studies of chimerism in human diseases have largely focused on diseases with a predilection for females including autoimmune diseases, and female cancers. We detail studies of chimerism in human diseases and also discuss some potential implications in behavior. Understanding the prevalence of chimerism and the associated health outcomes will provide invaluable knowledge of human biology and guide novel approaches for treating diseases.

Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer.

Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.

Cohabitation is associated with a greater resemblance in gut microbiota which can impact cardiometabolic and inflammatory risk.

BACKGROUND: The gut microbiota composition is known to be influenced by a myriad of factors including the host genetic profile and a number of environmental influences. Here, we focus on the environmental influence of cohabitation on the gut microbiota as well as whether these environmentally influenced microorganisms are associated with cardiometabolic and inflammatory burden. We perform this by investigating the gut microbiota composition of various groups of related individuals including cohabitating monozygotic (MZ) twin pairs, non-cohabitating MZ twin pairs and spouse pairs. RESULTS: A stronger correlation between alpha diversity was found in cohabitating MZ twins (45 pairs, r = 0.64, p = 2.21 × 10- 06) than in non-cohabitating MZ twin pairs (121 pairs, r = 0.42, p = 1.35 × 10- 06). Although the correlation of alpha diversity did not attain significance between spouse pairs (42 pairs, r = 0.23, p = 0.15), the correlation was still higher than those in the 209 unrelated pairs (r = - 0.015, p = 0.832). Bray-Curtis (BC) dissimilarity metrics showed cohabitating MZ twin pairs had the most similar gut microbiota communities which were more similar than the BC values of non-cohabitating MZ twins (empirical p-value = 0.0103), cohabitating spouses (empirical p-value = 0.0194), and pairs of unrelated non-cohabitating individuals (empirical p-value< 0.00001). There was also a significant difference between the BC measures from the spouse pairs and those from the unrelated non-cohabitating individuals (empirical p-value< 0.00001). Intraclass correlation coefficients were calculated between the various groups of interest and the results indicate the presence of OTUs with an environmental influence and one OTU that appeared to demonstrate genetic influences. One of the OTUs (Otu0190) was observed to have a significant association with both the cardiometabolic and inflammatory burden scores (p's < 0.05). CONCLUSIONS: Through the comparison of the microbiota contents of MZ twins with varying cohabitation status and spousal pairs, we showed evidence of environmentally influenced OTUs, one of which had a significant association with cardiometabolic and inflammatory burden scores.

Avera Twin Register Growing Through Online Consenting and Survey Collection.

The aim of the Avera Twin Register (ATR) is to establish a prospective longitudinal repository of twins, multiples, siblings and family members' biological samples to study environmental and genetic influences on health and disease. Also, it is our intention to contribute to international genome-wide association study (GWAS) twin consortia when appropriate sample size is achieved within the ATR. The ATR is young compared with existing registers and continues to collect a longitudinal repository of biological specimens, survey data and health information. Data and biological specimens were originally collected via face-to-face appointments or the postal department and consisted of paper-informed consents and questionnaires. Enrollment of the ATR began on May 18, 2016 and is located in Sioux Falls, South Dakota, a rural and frontier area in the Central United States with a regional population of approximately 880,000. The original target area for the ATR was South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota and Nebraska. The ATR has found a need to expand that area based on twin and multiple siblings who live in various areas surrounding these states. A description of the state of the ATR today and its transition to online data collection and informed consent will be presented. The ATR collects longitudinal data on lifestyle, including diet and activity levels, aging, plus complex traits and diseases. All twins and multiples participating in the ATR are genotyped on the Illumina Global Screening Array and receive zygosity results.

The Nigerian Twin and Sibling Registry: An Update.

Here we provide an update of the 2013 report on the Nigerian Twin and Sibling Registry (NTSR). The major aim of the NTSR is to understand genetic and environmental influences and their interplay in psychological and mental health development in Nigerian children and adolescents. Africans have the highest twin birth rates among all human populations, and Nigeria is the most populous country in Africa. Due to its combination of large population and high twin birth rates, Nigeria has one of the largest twin populations in the world. In this article, we provide current updates on the NTSR samples recruited, recruitment procedures, zygosity assessment and findings emerging from the NTSR.

Genetic Similarity Assessment of Twin-Family Populations by Custom-Designed Genotyping Array.

Twin registries often take part in large collaborative projects and are major contributors to genome-wide association (GWA) meta-analysis studies. In this article, we describe genotyping of twin-family populations from Australia, the Midwestern USA (Avera Twin Register), the Netherlands (Netherlands Twin Register), as well as a sample of mothers of twins from Nigeria to assess the extent, if any, of genetic differences between them. Genotyping in all cohorts was done using a custom-designed Illumina Global Screening Array (GSA), optimized to improve imputation quality for population-specific GWA studies. We investigated the degree of genetic similarity between the populations using several measures of population variation with genotype data generated from the GSA. Visualization of principal component analysis (PCA) revealed that the Australian, Dutch and Midwestern American populations exhibit negligible interpopulation stratification when compared to each other, to a reference European population and to globally distant populations. Estimations of fixation indices (FST values) between the Australian, Midwestern American and Netherlands populations suggest minimal genetic differentiation compared to the estimates between each population and a genetically distinct cohort (i.e., samples from Nigeria genotyped on GSA). Thus, results from this study demonstrate that genotype data from the Australian, Dutch and Midwestern American twin-family populations can be reasonably combined for joint-genetic analysis.

The Netherlands Twin Register: Longitudinal Research Based on Twin and Twin-Family Designs.

The Netherlands Twin Register (NTR) is a national register in which twins, multiples and their parents, siblings, spouses and other family members participate. Here we describe the NTR resources that were created from more than 30 years of data collections; the development and maintenance of the newly developed database systems, and the possibilities these resources create for future research. Since the early 1980s, the NTR has enrolled around 120,000 twins and a roughly equal number of their relatives. The majority of twin families have participated in survey studies, and subsamples took part in biomaterial collection (e.g., DNA) and dedicated projects, for example, for neuropsychological, biomarker and behavioral traits. The recruitment into the NTR is all inclusive without any restrictions on enrollment. These resources - the longitudinal phenotyping, the extended pedigree structures and the multigeneration genotyping - allow for future twin-family research that will contribute to gene discovery, causality modeling, and studies of genetic and cultural inheritance.

Associations between loneliness and personality are mostly driven by a genetic association with Neuroticism.

OBJECTIVE: Loneliness is an aversive response to a discrepancy between desired and actual social relationships and correlates with personality. We investigate the relationship of loneliness and personality in twin family and molecular genetic data. METHOD: Phenotypic correlations between loneliness and the Big Five personality traits were estimated in 29,625 adults, and in a group with genome-wide genotype data (N = 4,222), genetic correlations were obtained. We explored whether genetic correlations may reflect causal relationships by investigating within monozygotic twin pair differences (Npairs = 2,662), by longitudinal within-subject changes in personality and loneliness (N = 4,260-9,238 longitudinal comparisons), and by longitudinal cross-lagged panel analyses (N = 15,628). Finally, we tested whether genetic correlations were due to cross-trait assortative mating (Nspouse pairs = 4,436). RESULTS: The strongest correlations with loneliness were observed for Neuroticism (r = .55) and Extraversion (r = -.33). Only Neuroticism showed a high correlation with loneliness independent of other personality traits (r = .50), so follow-up analyses focused on Neuroticism. The genetic correlation between loneliness and Neuroticism from genotyped variants was .71; a significant reciprocal causal relationship and nonsignificant cross-trait assortative mating imply that this is at least partly due to mediated pleiotropy. CONCLUSIONS: We show that the relationship between loneliness and personality is largely explained by its relationship with Neuroticism, which is substantially genetic in nature.

An Extended Twin-Pedigree Study of Neuroticism in the Netherlands Twin Register.

For the participants in the Netherlands Twin Register (NTR) we constructed the extended pedigrees which specify all relations among nuclear and larger twin families in the register. A total of 253,015 subjects from 58,645 families were linked to each other, to the degree that we had information on the relations among participants. We describe the algorithm that was applied to construct the pedigrees. For > 30,000 adolescent and adult NTR participants data were available on harmonized neuroticism scores. We analyzed these data in the Mendel software package (Lange et al., Bioinformatics 29(12):1568-1570, 2013) to estimate the contributions of additive and non-additive genetic factors. In contrast to much of the earlier work based on twin data rather than on extended pedigrees, we could also estimate the contribution of shared household effects in the presence of non-additive genetic factors. The estimated broad-sense heritability of neuroticism was 47%, with almost equal contributions of additive and non-additive (dominance) genetic factors. A shared household effect explained 13% and unique environmental factors explained the remaining 40% of the variance in neuroticism.

Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas.

OBJECTIVE: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors. METHODS: We macro-dissected carcinomatous, sarcomatous, and normal tissues from formalin fixed paraffin embedded uterine samples of 10 UCS patients. Single nucleotide polymorphism microarrays, targeted DNA sequencing and whole-transcriptome RNA-sequencing were performed. Somatic chromosomal alterations (SCAs), point mutation and gene expression profiles were compared between carcinomatous and sarcomatous components. RESULTS: In addition to TP53, other recurrently mutated genes harboring putative driver or loss-of-function mutations included PTEN, FBXW7, FGFR2, KRAS, PIK3CA and CTNNB1, genes known to be involved in UCS. Intra-patient somatic mutation and SCA profiles were highly similar between paired carcinoma and sarcoma samples. An epithelial-mesenchymal transition (EMT) signature tended to differentiate components, with EMT-like status more common in advanced-stage patients exhibiting higher inter-component SCA heterogeneity. CONCLUSIONS: From DNA analysis, our results indicate a monoclonal disease origin for this cohort. Yet expression-derived EMT statuses of the carcinomatous and sarcomatous components were often discrepant, and advanced cases displayed greater genomic heterogeneity. Therefore, separately-profiled components of UCS tumors may better inform disease progression or potential.

Testing Familial Transmission of Smoking With Two Different Research Designs.

Introduction: Classical twin studies show that smoking is heritable. To determine if shared family environment plays a role in addition to genetic factors, and if they interact (G×E), we use a children-of-twins design. In a second sample, we measure genetic influence with polygenic risk scores (PRS) and environmental influence with a question on exposure to smoking during childhood. Methods: Data on smoking initiation were available for 723 children of 712 twins from the Netherlands Twin Register (64.9% female, median birth year 1985). Children were grouped in ascending order of risk, based on smoking status and zygosity of their twin-parent and his/her co-twin: never smoking twin-parent with a never smoking co-twin; never smoking twin-parent with a smoking dizygotic co-twin; never smoking twin-parent with a smoking monozygotic co-twin; and smoking twin-parent with a smoking or never smoking co-twin. For 4072 participants from the Netherlands Twin Register (67.3% female, median birth year 1973), PRS for smoking were computed and smoking initiation, smoking heaviness, and exposure to smoking during childhood were available. Results: Patterns of smoking initiation in the four group children-of-twins design suggested shared familial influences in addition to genetic factors. PRS for ever smoking were associated with smoking initiation in all individuals. PRS for smoking heaviness were associated with smoking heaviness in individuals exposed to smoking during childhood, but not in non-exposed individuals. Conclusions: Shared family environment influences smoking, over and above genetic factors. Genetic risk of smoking heaviness was only important for individuals exposed to smoking during childhood, versus those not exposed (G×E). Implications: This study adds to the very few existing children-of-twins (CoT) studies on smoking and combines a CoT design with a second research design that utilizes polygenic risk scores and data on exposure to smoking during childhood. The results show that shared family environment affects smoking behavior over and above genetic factors. There was also evidence for gene-environment interaction (G×E) such that genetic risk of heavy versus light smoking was only important for individuals who were also exposed to (second-hand) smoking during childhood. Together, these findings give additional incentive to recommending parents not to expose their children to cigarette smoking.

Metataxonomic Analysis of Individuals at BMI Extremes and Monozygotic Twins Discordant for BMI.

OBJECTIVE: The human gut microbiota has been demonstrated to be associated with a number of host phenotypes, including obesity and a number of obesity-associated phenotypes. This study is aimed at further understanding and describing the relationship between the gut microbiota and obesity-associated measurements obtained from human participants. SUBJECTS/METHODS: Here, we utilize genetically informative study designs, including a four-corners design (extremes of genetic risk for BMI and of observed BMI; N = 50) and the BMI monozygotic (MZ) discordant twin pair design (N = 30), in order to help delineate the role of host genetics and the gut microbiota in the development of obesity. RESULTS: Our results highlight a negative association between BMI and alpha diversity of the gut microbiota. The low genetic risk/high BMI group of individuals had a lower gut microbiota alpha diversity when compared to the other three groups. Although the difference in alpha diversity between the lean and heavy groups of the BMI-discordant MZ twin design did not achieve significance, this difference was observed to be in the expected direction, with the heavier participants having a lower average alpha diversity. We have also identified nine OTUs observed to be associated with either a leaner or heavier phenotype, with enrichment for OTUs classified to the Ruminococcaceae and Oxalobacteraceae taxonomic families. CONCLUSION: Our study presents evidence of a relationship between BMI and alpha diversity of the gut microbiota. In addition to these findings, a number of OTUs were found to be significantly associated with host BMI. These findings may highlight separate subtypes of obesity, one driven by genetic factors, the other more heavily influenced by environmental factors.

Establishment of the Avera Twin Register in the Midwest USA.

The Avera Twin Register (ATR) aims to study environmental and genetic influences on health and disease using a longitudinal repository of biological specimens, survey data, and health information provided by multiples and their family members. The ATR is located in Sioux Falls, South Dakota, which is a rural and frontier area in the Midwestern United States with a density of four people per square kilometer. The target area of the ATR is South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota, and Nebraska. Enrollment of twins and higher-order multiples of all ages and their family members started on May 18, 2016. A description of the first 13 months of enrollment in this longitudinal register will be provided. The ATR will collect longitudinal data on lifestyle, including diet and activity levels, aging, complex traits, and diseases. Upon registration, all participants are genotyped on the Illumina Global Screening Array (GSA) and twins and higher order multiples receive information on their zygosity. The ATR aims to contribute to large international GWAS consortia and collaborates closely with the Netherlands Twin Register, allowing for the comparison of collected data and analyses of results. In addition, the ATR will address twin-specific questions.

Genome-Wide Significance for PCLO as a Gene for Major Depressive Disorder.

In 2009, the first genome-wide association study (GWAS) for major depressive disorder (MDD) highlighted an association with PCLO locus on chromosome 7, although not reaching genome-wide significance level. In the present study, we revisited the original GWAS after increasing the overall sample size and the number of interrogated SNPs. In an analysis comparing 1,942 cases with lifetime diagnosis of MDD and 4,565 controls, PCLO showed a genome-wide significant association with MDD at SNP (rs2715157, p = 2.91 × 10-8) and gene-based (p = 1.48 × 10-7) level. Our results confirm the potential role of the PCLO gene in MDD, which is worth further replication and functional studies.

The Genetic Overlap Between Hair and Eye Color.

We identified the genetic variants for eye color by Genome-Wide Association Study (GWAS) in a Dutch Caucasian family-based population sample and examined the genetic correlation between hair and eye color using data from unrelated participants from the Netherlands Twin Register. With the Genome-wide Complex Trait Analysis software package, we found strong genetic correlations between various combinations of hair and eye colors. The strongest positive correlations were found for blue eyes with blond hair (0.87) and brown eyes with dark hair (0.71), whereas blue eyes with dark hair and brown eyes with blond hair showed the strongest negative correlations (-0.64 and -0.94, respectively). Red hair with green/hazel eyes showed the weakest correlation (-0.14). All analyses were corrected for age and sex, and we explored the effects of correcting for principal components (PCs) that represent ancestry and describe the genetic stratification of the Netherlands. When including the first three PCs as covariates, the genetic correlations between the phenotypes disappeared. This is not unexpected since hair and eye colors strongly indicate the ancestry of an individual. This makes it difficult to separate the effects of population stratification and the true genetic effects of variants on these particular phenotypes.