A multicentre review of the direct-access mammography programme in Ireland for women with breast pain.

AIM: To assess the current use of the direct access mammography pathway for breast pain and the rate of breast cancer detection in this patient cohort. MATERIALS AND METHODS: A retrospective review of general practitioner (GP)-referred mammograms performed during a 12-month period from January to December 2022 across four tertiary referral centres. With the use of medical records and GP referrals, patient demographics, presenting symptoms, family history, and clinical outcomes were recorded. RESULTS: The present study comprised 2,046 patients of which 21.6% did not report breast pain at the time of referral. Thirty-five per cent had a positive family history with 40% of these patients having no breast pain. Twelve per cent were recalled with 30% of these patients requiring biopsy. An overall cancer detection rate (CDR) of 7 per 1000 was determined for women with mastalgia. A CDR of 0 per 1,000 was determined for women <50 years with mastalgia alone and no additional risk factors for malignancy. Fisher's exact test showed no statistically significant association between breast pain and breast cancer. CONCLUSION: There was no statistically significant relationship found between breast pain and breast cancer. This review suggests a low cancer detection rate in women <50 years. In women <50 years with mastalgia without additional symptoms or family history, breast imaging is not required.

Fertility Preservation in Adolescent Males.

Aim Survival rates of childhood cancer are now above 80%, so there is increasing emphasis on survivorship. A major late effect of cancer treatment is fertility loss. International best practice indicates that post-pubertal boys with cancer should be offered sperm cryopreservation prior to treatment. The aim of this study was to demonstrate the feasibility of a national sperm cryopreservation program for adolescent males and to examine outcomes for a pilot. Methods Patient demographics and semen parameters of adolescent male oncology patients referred to our service were analysed. Sperm analyses were performed in accordance with WHO guidelines. Results Fifteen patients were referred, 12 of whom (80%) attempted sperm production. Of these 12 samples, 25% (3/12) were unsuitable for freezing. One patient was too unwell to produce a sample. Eight patients (age range 12-17 years) had sperm successfully cryopreserved. Of these 8 samples, 25% were within WHO 'normal' limits, 50% had reduced sperm concentration. The number of cryopreserved samples (straws) ranged from 4-8 per patient. Conclusion We have established a successful, structured fertility preservation service for adolescent males in Ireland. Sperm cryopreservation is an accessible method of safeguarding fertility in male patients facing cancer treatment and should be offered to all.

Five-year follow up of a low glycaemic index dietary randomised controlled trial in pregnancy-no long-term maternal effects of a dietary intervention.

OBJECTIVE: To determine whether a dietary intervention in pregnancy had a lasting effect on maternal outcomes of diet, HbA1c and weight retention 5 years post-intervention; and to establish whether modifiable maternal behaviours were associated with these outcomes. DESIGN: Randomised control trial of low glycaemic index (GI) diet in pregnancy with longitudinal follow up to 5 years post-intervention. SETTING: Dublin, Ireland (2007-2016). POPULATION: In all, 403 women of 759 (53.1%) were followed up at 5 years. A total of 370 (intervention n = 188; control n = 182) were included in this analysis. METHODS: Fasting glucose was measured at 13 and 28 weeks' gestation and HbA1c (mmol/mol) at 5-year follow up. Weight retention (kg) from early pregnancy to 5 years post-intervention was calculated. Dietary intakes, anthropometry, and lifestyle factors were measured in pregnancy and 5 years post-intervention. Multiple linear regression models, controlling for confounders, were used for analysis. OUTCOME: Maternal diet, HbA1c, and weight retention at 5 years post-intervention. RESULTS: There was no difference between the intervention and control at 5 years post-intervention for any long-term maternal outcomes measured. HbA1c at 5 years post-intervention was associated with early-pregnancy fasting glucose (B 1.70, 95% CI 0.36-3.04) and parity ≥3 (B 1.04, 95% CI 0.09-1.99). Weight retention was associated with change in well-being from pregnancy to 5 years (B -0.06, 95% CI -0.11 to -0.02), gestational weight gain (B 0.19, 95% CI 0.00-0.38), and GI (B 0.26, 95% CI 0.06-0.46) at 5 years. CONCLUSIONS: The ROLO low-GI dietary intervention in pregnancy had no impact on maternal dietary intakes, HbA1c or body composition 5 years post-intervention. Maternal factors and lifestyle behaviours in pregnancy have long-term effects on glucose metabolism and weight retention up to 5 years later. TWEETABLE ABSTRACT: Pregnancy factors are associated with maternal glucose metabolism and weight retention 5 years later-findings from the ROLO Study.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences.

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging.

The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12-18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

A novel association between COMT and BDNF gene polymorphisms and likelihood of symptomatic dysphagia in older people.

BACKGROUND: Catechol-O-methyl transferase (COMT) and brain-derived neurotrophic factor (BDNF) are neuro-modulatory proteins that have been demonstrated to affect cortical plasticity, which in turn has been shown to affect age-related changes and neuronal functioning in humans. Here, we tested the hypothesis that single nucleotide polymorphisms (SNP) within COMT and BDNF genes are associated with dysphagia in older adults. METHODS: A total of 800 community-dwelling older individuals were sent the Sydney Oropharyngeal Dysphagia Questionnaire to identify swallowing difficulties. DNA from this population was available for study and used to genotype 18 COMT and 12 BDNF polymorphisms. Logistic regression statistical models were used to identify potential associations between dysphagia and the genotypes. KEY RESULTS: A total of 638 individuals completed the questionnaire, giving an 80% response rate. Of these, 538 were genotyped for COMT and BDNF polymorphisms. Age was found to predict dysphagia (p = 0.018, OR = 1.08, CI = 1.01-1.14). The COMT polymorphism rs165599 and the BDNF polymorphism rs10835211 were found to predict dysphagia and have an interactive effect (p = 0.028), which varied according to the carrier status of the other. In the case of SNP rs10835211, the effect of heterozygosity was protective or harmful dependent on the respective status of rs165599. CONCLUSIONS & INFERENCES: These results suggest that certain interactions between plasticity genes contribute to the development of dysphagia with increasing age. This highlights a possible role for genetic factors in future monitoring and treating individuals affected by dysphagia.

Methodologies to assess paediatric adiposity.

INTRODUCTION: Childhood obesity is associated with increased risk of adult obesity, cardiovascular disease, diabetes and cancer. Appropriate techniques for assessment of childhood adiposity are required to identify children at risk. The aim of this review was to examine core clinical measurements and more technical tools to assess paediatric adiposity. METHODS: The online databases PubMed, CINALH and EMBASE were searched and the abstracts identified were reviewed to determine appropriate studies. Their reference lists were also searched to identify further eligible studies. Publications were included if they described childhood measurement techniques or involved validation. RESULTS AND DISCUSSION: There are many body composition assessment tools available, none of which are direct. Each technique has limitations and a combination of methods may be used. The main clinical techniques are weight, height, body mass index (BMI) and circumferences which provide sufficient information to enable classification of overweight or obesity when growth centile charts and ratios are employed. Further investigation depends on resources available and examiner skill. Skinfold thicknesses are cost-effective but require technical training and only measure subcutaneous fat. Dual energy X-ray absorptiometry (DEXA), air displacement plethysmography (ADP), magnetic resonance imaging (MRI) and computed tomography (CT) are more costly and intensive, requiring the child to remain still for longer periods. DEXA and ADP are capable of accurately measuring adiposity but are unable to distinguish between fat depots. MRI and CT can distinguish intra-abdominal from subcutaneous adiposity and are considered gold standards, but CT is unsuitable for adiposity measurement in children due to high levels of radiation exposure. Ultrasound is a promising technique capable of measuring intra-abdominal adiposity in children but requires further validation. CONCLUSION: The core clinical measurements of weight, height, BMI and circumferences are sufficient to enable diagnosis of paediatric overweight and obesity while more technical tools provide further insight.

Homozygosity in the ApoE 4 polymorphism is associated with dysphagic symptoms in older adults.

Apolipoprotein E (ApoE) is the most well-described genetic risk factor for Alzheimer's disease and nonpathological cognitive decline. While possession of the E2 allele may have protective properties, substantial research evidence suggests the E4 allele increases the risk of cognitive degeneration. As neurodegenerative processes are implicated in swallowing dysfunction, we hypothesized that the presence of ApoE 4 would be predictive of dysphagia symptoms in older adults. Eight hundred members of a genetically well characterized community dwelling elderly cohort received the Sydney oropharyngeal dysphagia questionnaire via mail. Cognitive function was also measured using the modified Telephone Interview of Cognitive Status (TiCS-m) and depression with the Geriatric Depression Score (GDS). ApoE allele was genotyped on blood samples from all subjects and data analyzed using standard statistical software (SPSS version 16). Completed questionnaire response rate was 79% (23.5% men, 76.5% women; mean age 81 ± 5 years; range 69-98 years). Possession of one or more of the ApoE 4 and 2 alleles was found in 23.5% and 16%, respectively. Swallowing score was significantly related to GDS (rho 0.133, P < 0.001**) and age (rho 0.107, P < 0.007**) but not general cognitive function as measured by TICS-m. Self-reported swallowing function was not significantly associated with heterozygosity of any allele or homozygosity for E2 or E3 alleles. Although infrequent (1.1% of all subjects) ApoE E4 homozygosity was significantly associated with higher swallowing scores compared to all other allele combinations (P = 0.033) and while attenuated, was still predicted in multivariate regression modeling (B = 0.812; SE = 0.323; P = 0.012). We report the association between ApoE 4 homozygous genotype and self-reported oropharyngeal dysphagia symptoms in community-dwelling older adults. As this association is weakened by the multivariate analysis and the population frequency of ApoE 4 allele homozygosity is low, this finding while intriguing requires replication in larger independent cohorts.

GWAS-based pathway analysis differentiates between fluid and crystallized intelligence.

Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Well-being in pregnancy: an examination of the effect of socioeconomic, dietary and lifestyle factors including impact of a low glycaemic index dietary intervention.

BACKGROUND/OBJECTIVE: Well-being has been linked to the quality of diet and lifestyle in adults; however, there is a paucity of data in pregnancy. The aim of this study was to examine the relationship between well-being and socioeconomic status, diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index (GI) diet on well-being. SUBJECTS/METHODS: This was a cohort analysis of 619 participants of the ROLO study (Randomised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia). The following data were collected: educational attainment, dietary intakes (food frequency questionnaire), physical activity (self-reported) and well-being (WHO-5-Item Wellbeing Index--expressed as a percentage). RESULTS: Well-being was positively associated with education and physical activity. Third-level education was associated with a 3.07-point higher well-being percentage score, and each day that an individual achieved >30 min walking per week was associated with a 1.10-point increase in percentage well-being score, Radj(2) 2.4% (F=7.260, P=0.001). The intervention low GI group had a significantly lower percentage well-being score than the usual diet group (56.3% vs 59.9%, P=0.015). No correlation was noted between well-being and GI status calculated from food diaries (P=0.469). Well-being was not associated with micronutrient intake. CONCLUSIONS: Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention. These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk.

AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes.

Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion.

The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<~2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ~12,000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e. = 0.03) for neuroticism and 0.12 (s.e. = 0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ~45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called 'missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.