Predicting educational achievement from DNA.

This corrects the article DOI: 10.1038/mp.2016.107.

Multi-polygenic score approach to trait prediction.

A primary goal of polygenic scores, which aggregate the effects of thousands of trait-associated DNA variants discovered in genome-wide association studies (GWASs), is to estimate individual-specific genetic propensities and predict outcomes. This is typically achieved using a single polygenic score, but here we use a multi-polygenic score (MPS) approach to increase predictive power by exploiting the joint power of multiple discovery GWASs, without assumptions about the relationships among predictors. We used summary statistics of 81 well-powered GWASs of cognitive, medical and anthropometric traits to predict three core developmental outcomes in our independent target sample: educational achievement, body mass index (BMI) and general cognitive ability. We used regularized regression with repeated cross-validation to select from and estimate contributions of 81 polygenic scores in a UK representative sample of 6710 unrelated adolescents. The MPS approach predicted 10.9% variance in educational achievement, 4.8% in general cognitive ability and 5.4% in BMI in an independent test set, predicting 1.1%, 1.1%, and 1.6% more variance than the best single-score predictions. As other relevant GWA analyses are reported, they can be incorporated in MPS models to maximize phenotype prediction. The MPS approach should be useful in research with modest sample sizes to investigate developmental, multivariate and gene-environment interplay issues and, eventually, in clinical settings to predict and prevent problems using personalized interventions.

Predicting educational achievement from DNA.

A genome-wide polygenic score (GPS), derived from a 2013 genome-wide association study (N=127,000), explained 2% of the variance in total years of education (EduYears). In a follow-up study (N=329,000), a new EduYears GPS explains up to 4%. Here, we tested the association between this latest EduYears GPS and educational achievement scores at ages 7, 12 and 16 in an independent sample of 5825 UK individuals. We found that EduYears GPS explained greater amounts of variance in educational achievement over time, up to 9% at age 16, accounting for 15% of the heritable variance. This is the strongest GPS prediction to date for quantitative behavioral traits. Individuals in the highest and lowest GPS septiles differed by a whole school grade at age 16. Furthermore, EduYears GPS was associated with general cognitive ability (~3.5%) and family socioeconomic status (~7%). There was no evidence of an interaction between EduYears GPS and family socioeconomic status on educational achievement or on general cognitive ability. These results are a harbinger of future widespread use of GPS to predict genetic risk and resilience in the social and behavioral sciences.

Phenome-wide analysis of genome-wide polygenic scores.

Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents' behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development.

How specific is second language-learning ability? A twin study exploring the contributions of first language achievement and intelligence to second language achievement.

Learning a second language is crucially important in an increasingly global society, yet surprisingly little is known about why individuals differ so substantially in second language (SL) achievement. We used the twin design to assess the nature, nurture and mediators of individual differences in SL achievement. For 6263 twin pairs, we analyzed scores from age 16 UK-wide standardized tests, the General Certificate of Secondary Education (GCSE). We estimated genetic and environmental influences on the variance of SL for specific languages, the links between SL and English and the extent to which the links between SL and English are explained by intelligence. All SL measures showed substantial heritability, although heritability was nonsignificantly lower for German (36%) than the other languages (53-62%). Multivariate genetic analyses indicated that a third of genetic influence in SL is shared with intelligence, a third with English independent of intelligence and a further third is unique to SL.

Synchronous lobular carcinoma in situ and invasive lobular cancer: marker or precursor for invasive lobular carcinoma.

AIM: Lobular carcinoma in situ (LCIS) is a known risk factor for invasive breast carcinoma, but there is increasing data indicating a possible precursor relationship. This study investigates the incidence of lobular carcinoma in situ that occurs with invasive lobular carcinoma (ILC). METHODS: Women diagnosed with ILC or LCIS from 2000 to 2010 were retrospectively identified and reviewed after institutional review board approval. This group was divided into two cohorts: ILC alone, and LCIS and ILC (ILC/LCIS). Patient demographics, disease characteristics, and treatment modalities were captured. p < 0.05 is considered significant. RESULTS: A total of 148 patients with ILC or LCIS were identified. Forty-four (54%) patients with only ILC, and 37 (46%) patients with ILC/LCIS were identified. Median age at diagnosis was 62 for ILC and 64 years for ILC/LCIS (p = 0.8). In patients with ILC, total mastectomy was the predominant treatment modality in 28 of 44 (64%) patients, while 18 of 37 (49%) patients with ILC/LCIS underwent breast conservation therapy (p = 0.3). Median largest tumor diameter was 35 mm (range 1-110) for ILC, and 15 mm (range 5-85) for ILC/LCIS (p = 0.03). Nodal status was positive in 17 of 39 (44%) ILC and 13 of 34 (38%) ILC/LCIS (p = 0.6). CONCLUSIONS: The 46% incidence of LCIS associated with ILC in our cohort study is similar to that reported for ductal carcinoma in situ identified with invasive ductal carcinoma at ∼40%. The association of pre-invasive and invasive lobular lesions should be further studied in a large scale prospective study to assess for a precursor relationship.

A genome-wide association study identifies multiple loci associated with mathematics ability and disability.

Numeracy is as important as literacy and exhibits a similar frequency of disability. Although its etiology is relatively poorly understood, quantitative genetic research has demonstrated mathematical ability to be moderately heritable. In this first genome-wide association study (GWAS) of mathematical ability and disability, 10 out of 43 single nucleotide polymorphism (SNP) associations nominated from two high- vs. low-ability (n = 600 10-year-olds each) scans of pooled DNA were validated (P < 0.05) in an individually genotyped sample of (*)2356 individuals spanning the entire distribution of mathematical ability, as assessed by teacher reports and online tests. Although the effects are of the modest sizes now expected for complex traits and require further replication, interesting candidate genes are implicated such as NRCAM which encodes a neuronal cell adhesion molecule. When combined into a set, the 10 SNPs account for 2.9% (F = 56.85; df = 1 and 1881; P = 7.277e-14) of the phenotypic variance. The association is linear across the distribution consistent with a quantitative trait locus (QTL) hypothesis; the third of children in our sample who harbour 10 or more of the 20 risk alleles identified are nearly twice as likely (OR = 1.96; df = 1; P = 3.696e-07) to be in the lowest performing 15% of the distribution. Our results correspond with those of quantitative genetic research in indicating that mathematical ability and disability are influenced by many genes generating small effects across the entire spectrum of ability, implying that more highly powered studies will be needed to detect and replicate these QTL associations.

Generalist genes and the Internet generation: etiology of learning abilities by web testing at age 10.

A key translational issue for neuroscience is to understand how genes affect individual differences in brain function. Although it is reasonable to suppose that genetic effects on specific learning abilities, such as reading and mathematics, as well as general cognitive ability (g), will overlap very little, the counterintuitive finding emerging from multivariate genetic studies is that the same genes affect these diverse learning abilities: a Generalist Genes hypothesis. To conclusively test this hypothesis, we exploited the widespread access to inexpensive and fast Internet connections in the UK to assess 2541 pairs of 10-year-old twins for reading, mathematics and g, using a web-based test battery. Heritabilities were 0.38 for reading, 0.49 for mathematics and 0.44 for g. Multivariate genetic analysis showed substantial genetic correlations between learning abilities: 0.57 between reading and mathematics, 0.61 between reading and g, and 0.75 between mathematics and g, providing strong support for the Generalist Genes hypothesis. If genetic effects on cognition are so general, the effects of these genes on the brain are also likely to be general. In this way, generalist genes may prove invaluable in integrating top-down and bottom-up approaches to the systems biology of the brain.

Overlap and specificity of genetic and environmental influences on mathematics and reading disability in 10-year-old twins.

BACKGROUND: To what extent do genetic and environmental influences on reading disability overlap with those on mathematics disability? Multivariate genetic research on the normal range of variation in unselected samples has led to a Generalist Genes Hypothesis which posits that the same genes largely affect individual differences in these abilities in the normal range. However, little is known about the etiology of co-morbidity for the disability extremes of reading and mathematics. METHOD: From 2596 pairs of 10-year-old monozygotic and dizygotic twins assessed on a web-based battery of reading and mathematics tests, we selected the lowest 15% on reading and on mathematics. We conducted bivariate DeFries-Fulker (DF) extremes analyses to assess overlap and specificity of genetic and environmental influences on reading and mathematics disability defined by a 15% cut-off. RESULTS: Both reading and mathematics disability are moderately heritable (47% and 43%, respectively) and show only modest shared environmental influence (16% and 20%). There is substantial phenotypic co-morbidity between reading and mathematics disability. Bivariate DF extremes analyses yielded a genetic correlation of .67 between reading disability and mathematics disability, suggesting that they are affected largely by the same genetic factors. The shared environmental correlation is .96 and the non-shared environmental correlation is .08. CONCLUSIONS: In line with the Generalist Genes Hypothesis, the same set of generalist genes largely affects mathematical and reading disabilities. The dissociation between the disabilities occurs largely due to independent non-shared environmental influences.

Association analysis of mild mental impairment using DNA pooling to screen 432 brain-expressed single-nucleotide polymorphisms.

We hypothesize that mild mental impairment (MMI) represents the low extreme of the same quantitative trait loci (QTLs) that operate throughout the distribution of intelligence. To detect QTLs of small effect size, we employed a direct association strategy by genotyping 432 presumably functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) identified from public databases on DNA pools of 288 cases and 1025 controls. In total, 288 MMI cases were identified by in-home administration of McCarthy Scales of Children's Abilities to 836 twin pairs selected from a community sample of more than 14 000 children previously screened for nonverbal cognitive delay using parentally administered tests. Controls were selected from the community sample representing the full range of nonverbal intelligence. SNPs showing at least 7% allele frequency differences between case and control DNA pools were tested for their association with the full range of nonverbal intelligence using five DNA subpools, each representing quintiles of the normal quantitative trait scores from the 1025 controls. SNPs showing linear associations in the expected direction across quintiles using pooled DNA were individually genotyped for the 288 cases and 1025 controls and analyzed using standard statistical methods. One SNP (rs1136141) in HSPA8 met these criteria, yielding a significant (P=0.036) allelic frequency difference between cases and controls for individual genotyping and a significant (P=0.013) correlation within the control group that accounts for 0.5% of the variance. The present SNP strategy combined with DNA pooling and large samples represents a step towards identifying QTLs of small effect size associated with complex traits in the postgenomic era when all functional polymorphisms will be known.

Language-impaired children: No sign of the FOXP2 mutation.

A mutation in the FOXP2 gene has been found to be responsible for the autosomal dominant inheritance of a severe form of speech and language impairment in a family known as KE. We genotyped the FOXP2 mutation for 270 4-year-old children selected for low general language scores from a representative community sample of more than 18,000 children. No language-impaired child had the FOXP2 mutation. Although rare severe disorders such as those of the KE family are often caused by a single gene, common disorders such as language impairment are more likely to be the quantitative extreme of the same multiple genetic factors responsible for heritability throughout the distribution.

Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects.

PURPOSE: The use of additional therapy with an oral enzyme preparation containing trypsin, chymotrypsin and papain has been suggested for the reduction of toxicity due to radiation therapy. This study was conducted to test the efficacy and tolerability of this enzyme combination in preventing or reducing the acute side effects of radiation therapy in patients with locally advanced cervical cancer. METHODS: A prospective, randomised, open, clinical trial was carried out on 120 patients (aged 24-85 years) with locally advanced, biopsy-proven carcinomas of the uterine cervix (stages IIa, lIb or IIIb). Patients received 50 Gy of external radiation therapy over a period of 5 weeks, followed by intracavitary brachytherapy (20-30 Gy). Patients assigned to the test group (60 patients) received additional treatment with enzymes. Patients were evaluated at weekly intervals for acute radiation therapy-related side effects, according to the RTOG/EORTC grading criteria, and then after the end of radiation therapy for another 8 weeks. Occurrence of adverse events, if any, was also recorded. RESULTS: The study revealed that the maximum extent of acute radiation side effects was reduced in the enzyme group: skin reactions (mean: 0.97 vs 1.68 in the control group, P < 0.001), vaginal mucosal reactions (0.55 vs 0.85, P = 0.10), genitourinary symptoms (0.93 vs 1.38, P < 0.001) and gastrointestinal reactions (1.12 vs 1.30, P = 0.12). The sum-scores during treatment, expressed as area under the curve, were significantly less in the enzyme treated patients. In the follow-up visits all observed side effects of radiation therapy were of lower intensity in the enzyme group than in the control group. CONCLUSIONS: In patients with locally advanced cancer of the uterine cervix, oral enzyme therapy was found to be effective in significantly reducing radiation therapy-related side effects such as genitourinary symptoms, subcutaneous changes and reactions of the vaginal mucosa.

Lexical and grammatical development: a behavioural genetic perspective.

The relation of lexical and grammatical knowledge is at the core of many controversies in linguistics and psycholinguistics. Recent empirical findings that the two are highly correlated in early language development have further energized the theoretical debate. Behavioural genetics provides an illuminating new tool to explore this question, by addressing the question of whether the empirical correlation simply reflects the fact that environments which facilitate one aspect of language growth also facilitate the other, or whether the same underlying acquisition mechanisms, influenced by the same genes, are responsible for the correlation. We explored this issue in a study of 2898 pairs of two-year-old twins born in England and Wales. Language development was assessed by their parents using an adapted version of the MacArthur Communicative Development Inventory which assesses vocabulary and grammar. Moderate heritabilities were found for both. As in previous studies, measures of vocabulary and sentence complexity were substantially correlated (r = 0.66). Behaviour-genetic modelling of the relation of vocabulary and grammar produced an estimated value of 0.61 for the genetic correlation, a measure of the overlap of the genetic effects that contribute to the two aspects of language development. In contrast, a measure of nonverbal cognitive development, the PARCA, was only weakly correlated at both the phenotypic level and at the level of genetic correlations with the language measures. Thus, although the distinction between verbal and nonverbal skills has a genetic basis underlying the phenotypic dissociation, there is little evidence either genetically or phenotypically for a dissociation between vocabulary and grammar within language.

Genetic and environmental covariation between verbal and nonverbal cognitive development in infancy.

Despite cognitive neuroscience's emphasis on the modularity of cognitive processes, multivariate genetic research indicates that the same genetic factors largely affect diverse cognitive abilities, at least from middle childhood onward. We explored this issue for verbal and nonverbal cognitive development in infancy in a study of 1,937 pairs of same-sex 2-year-old twins born in England and Wales in 1994. The twins were assessed by having their parents use a measure of productive vocabulary (the MacArthur Communicative Development Inventory) and a novel measure of nonverbal cognitive abilities (Parent Report of Children's Ability). Verbal and nonverbal development correlated .42. A multivariate genetic analysis indicated that genetic factors were responsible for less than half of this phenotypic correlation. Moreover, the genetic correlation between verbal and nonverbal abilities was only .30, which indicates that genetic effects on verbal and nonverbal abilities are largely independent in infancy. These multivariate genetic results suggest that genetic effects on cognitive abilities are modular early in development and then become increasingly molar. The implications of this result for theories of cognitive development are discussed.

Sentinel lymphadenectomy for staging patients with intermediate-level melanoma.

Sentinel lymph node dissection (SLND) as originally described by D.L. Morton et al. (Surg Oncol Clin North Am 1992;1:247-59), is currently being used at most tertiary institutions for staging patients with intermediate-level melanomas. Identification and subsequent surgical resection of occult metastasis before the development of clinical disease may improve survival in these patients. This study is a retrospective review of patients with intermediate melanomas treated by the senior author (P.S.D.). Isosulfan blue dye and a radioactive technetium-labeled dye were used to identify the sentinel node. Sentinel nodes were evaluated by routine hematoxylin and eosin staining, immunohistochemical staining for S-100 and HMB-45, and later in the study with multipanel reverse transcriptase-polymerase chain reaction analysis. All patients were followed closely. Fifty-seven patients with primary melanoma were evaluated between December 1995 and June 1998. Thirty-two patients underwent SLND; two patients underwent SLND on two separate drainage basins, for a total of 34 procedures. The median age was 49 years (range, 19-77). There were 11 females and 21 males. The locations of the primary melanoma were: head and neck, seven; extremity, 8; and trunk, 18; 1 patient had a dual primary melanoma at presentation. Clark's levels of invasion among the patients were level III, 5; and level IV, 27; median Breslow thickness was 1.4 mm (range, 0.45-3.8 mm). A sentinel node was not identified in four procedures (11.1%). Twenty-two nodes (73%) were negative by all methods, and eight (27%) were positive by at least one method. All positive patients underwent complete lymphadenectomy, and routine hematoxylin and eosin stains identified no additional positive nodes. Median follow-up was 21 months (6-36 months). Two patients developed recurrent disease. The other 30 patients remain disease free at last follow-up. SLND is a low-morbidity technique that accurately stages patients with intermediate-level melanoma. Early intervention with complete therapeutic lymphadenectomy and possible interferon therapy may improve the survival of patients with stage III melanoma. A complete discussion of the technique for SLND and an update of this data is presented.

Genetic and environmental origins of verbal and performance components of cognitive delay in 2-year-olds.

The authors investigated the etiology of several measures of cognitive delay. Verbal (V) and performance (P) abilities were assessed in over 3,000 pairs of 2-year-old twins. Group-differences heritability for general delay (the lowest 5% of the V and P composite) was 35%. However, V and P delays considered independently showed large differences in group heritability (77% for V vs. 40% for P). Specific delays with comorbid cases eliminated showed an even greater difference in group heritability (78% vs. 22%, respectively). The small sample comorbid for both V and P delay also yielded high group heritability for both V (77%) and P (93%) scores. Shared environmental factors also differed in magnitude for V (20%) and P (41%) delays. Because the genetic and environmental origins of V and P delays in infancy differ, they are better considered separately rather than combined into a composite measure of general cognitive delay.

Cryosurgical ablation of unresectable hepatic metastases.

BACKGROUND AND OBJECTIVES: Recent advancements in the technology of cryosurgery along with the development and refinement of intraoperative ultrasound have led to a feasible alternative for some patients with unresectable hepatic malignancy. This paper reports our first year's experience with cryosurgical ablation of unresectable hepatic malignancies. METHODS: From May 1996 to July 1997, 12 patients with colorectal hepatic metastases underwent exploration for possible resection and/or cryosurgery. At surgery, three patients had extensive disease and were not candidates for any surgical treatment, three underwent formal right hepatic lobectomy, five underwent a combination of resection and cryoablation, while one underwent cryoablation alone. RESULTS: In the six patients who received cryosurgery, the mean number of metastatic lesions was four (range 1-6). The mean number of lesions frozen was two (range 1-4) with a mean size of 2.5 cm. (range 1-5 cm). There were no intraoperative deaths and no major postoperative complications. All patients were discharged home in stable condition with a mean hospital stay of eight days (range 5-14 days). At a mean follow-up of 17.3 months (range 10-22) three patients were alive with disease and three were disease free. CONCLUSIONS: Cryosurgical ablation is a safe method of treating unresectable hepatic malignancies and it may extend survival in carefully selected patients.

Axillary staging utilizing selective sentinel lymphadenectomy for patients with invasive breast carcinoma.

The clinical staging of the regional lymphatics in patients with breast carcinoma is currently receiving much attention in the medical literature. However, controversy still exists regarding surgical staging of the axilla. Most recently, the technique of selective sentinel lymphadenectomy has been applied to staging of breast carcinoma. Our experience with this technique is presented. From July 1, 1995 through December 31, 1996, 20 patients underwent 21 selective sentinel lymphadenectomies prior to level I, level II, and partial level III axillary dissections. There were 13 modified radical mastectomies and 8 segmental mastectomies. The median number of lymph nodes per specimen was 9 (range, 1-31). The sentinel node was identified in 14 patients (66%). Dual sentinel nodes were identified during 3 procedures. The sentinel nodes were negative in 9 procedures, of which all axillary nodes dissected were negative. The sentinel node was positive in 5 procedures for a 100 per cent predictive value. The sentinel node was the only positive node in 3 of the 5 patients, and 2 of these were microscopic (less than 2 mm). There were no associated complications due to the sentinel node biopsy. These results add to the growing literature supporting the feasibility of the sentinel node technique for accurately staging breast carcinoma. This technique is sensitive and specific and can be performed with minimal morbidity.

Genetic influence on language delay in two-year-old children.

Previous work suggests that most clinically significant language difficulties in children do not result from acquired brain lesions or adverse environmental experiences but from genetic factors that presumably influence early brain development. We conducted the first twin study of language delay to evaluate whether genetic and environmental factors at the lower extreme of delayed language are different from those operating in the normal range. Vocabulary at age two was assessed for more than 3000 pairs of twins. Group differences heritability for the lowest 5% of subjects was estimated as 73% in model-fitting analyses, significantly greater than the individual differences heritability for the entire sample (25%). This supports the view of early language delay as a distinct disorder. Shared environment was only a quarter as important for the language-delayed sample (18%) as for the entire sample (69%).