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1.  [No title available] 
PMCID: PMC3984901  PMID: 24398790
2.  [No title available] 
PMCID: PMC4096149  PMID: 24281372
3.  Dynamic consent: a patient interface for twenty-first century research networks 
Biomedical research is being transformed through the application of information technologies that allow ever greater amounts of data to be shared on an unprecedented scale. However, the methods for involving participants have not kept pace with changes in research capability. In an era when information is shared digitally at the global level, mechanisms of informed consent remain static, paper-based and organised around national boundaries and legal frameworks. Dynamic consent (DC) is both a specific project and a wider concept that offers a new approach to consent; one designed to meet the needs of the twenty-first century research landscape. At the heart of DC is a personalised, digital communication interface that connects researchers and participants, placing participants at the heart of decision making. The interface facilitates two-way communication to stimulate a more engaged, informed and scientifically literate participant population where individuals can tailor and manage their own consent preferences. The technical architecture of DC includes components that can securely encrypt sensitive data and allow participant consent preferences to travel with their data and samples when they are shared with third parties. In addition to improving transparency and public trust, this system benefits researchers by streamlining recruitment and enabling more efficient participant recontact. DC has mainly been developed in biobanking contexts, but it also has potential application in other domains for a variety of purposes.
doi:10.1038/ejhg.2014.71
PMCID: PMC4130658  PMID: 24801761
4.  Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP 
The presence of multiple (5–100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10−7). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have ‘polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.
doi:10.1038/ejhg.2014.74
PMCID: PMC4140766  PMID: 24801760
5.  Microcephaly with or without Chorioretinopathy, Lymphoedema or Mental Retardation (MCLMR); review of phenotype associated with KIF11 mutations 
Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM #152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in sixteen families worldwide. This is a review of the condition based on the clinical features of thirty seven individuals from twenty two families. This report includes nine previously unreported families and additional information for some of those reported previously.
The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied, and include missense, nonsense, frameshift and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations, but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.
doi:10.1038/ejhg.2013.263
PMCID: PMC3938398  PMID: 24281367
Microcephaly; Chorioretinal dysplasia; Lymphoedema; KIF11; MCLMR
6.  A unifying framework for robust association testing, estimation, and genetic model selection using the generalized linear model 
European Journal of Human Genetics  2013;21(12):1442-1448.
The analysis of genome-wide genetic association studies generally starts with univariate statistical tests of each single-nucleotide polymorphism. The standard approach is the Cochran-Armitage trend test or its logistic regression equivalent although this approach can lose considerable power if the underlying genetic model is not additive. An alternative is the MAX test, which is robust against the three basic modes of inheritance. Here, the asymptotic distribution of the MAX test is derived using the generalized linear model together with the Delta method and multiple contrasts. The approach is applicable to binary, quantitative, and survival traits. It may be used for unrelated individuals, family-based studies, and matched pairs. The approach provides point and interval effect estimates and allows selecting the most plausible genetic model using the minimum P-value. R code is provided. A Monte-Carlo simulation study shows that the asymptotic MAX test framework meets type I error levels well, has good power, and good model selection properties for minor allele frequencies ≥0.3. Pearson's χ2-test is superior for lower minor allele frequencies with low frequencies for the rare homozygous genotype. In these cases, the model selection procedure should be used with caution. The use of the MAX test is illustrated by reanalyzing findings from seven genome-wide association studies including case–control, matched pairs, and quantitative trait data.
doi:10.1038/ejhg.2013.62
PMCID: PMC3820468  PMID: 23572026
family-based association; genetic association; genome-wide association; indirect mapping; MAX test
7.  Homozygosity analysis in amyotrophic lateral sclerosis 
European Journal of Human Genetics  2013;21(12):1429-1435.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10−5), a greater proportion of cases harboured homozygosity (P=2 × 10−5), a longer average length of segment (P=1 × 10−5), a longer total genome coverage (P=1 × 10−5), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; recessive
8.  Prepubertal start of father's smoking and increased body fat in his sons: further characterisation of paternal transgenerational responses 
European Journal of Human Genetics  2014;22(12):1382-1386.
Despite interest in the idea that transgenerational effects of adverse exposures might contribute to population health trends, there are few human data. This non-genetic inheritance is all the more remarkable when transmission is down the male-line as reported in a historical Swedish study, where the paternal grandfather's food supply in mid childhood was associated with the mortality rate in his grandsons. Using the Avon Longitudinal Study of Parents and Children's questionnaire data on smoking and smoking onset from 9886 fathers, we examined the growth of their children from 7–17 years. Adjusting for potential confounders, we assessed associations between body mass index (BMI), waist circumference, total fat mass and lean mass with the age at which the father had started smoking regularly. Of 5376 fathers who reported having ever smoked, 166 reported regular smoking <11 years of age. Before adjustment, those offspring whose fathers started smoking <11 years had the highest mean BMIs at each age tested. The adjusted mean differences in BMI, waist circumference and total fat mass in those sons whose fathers started smoking <11 years, compared with all other sons, increased with age, being significantly greater from 13 years onwards. There were no significant BMI associations in daughters, but they showed a reduction in total lean mass. Our results highlight the importance of the developmental timing of the paternal exposure as well as gender differences in offspring outcomes. Smoking by boys in mid childhood may contribute to obesity in adolescent boys of the next generation.
doi:10.1038/ejhg.2014.31
PMCID: PMC4085023  PMID: 24690679
9.  Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias 
European Journal of Human Genetics  2014;22(11):1278-1282.
Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) are chondrodysplasias resulting in short-limbed dwarfism, joint pain and stiffness and early onset osteoarthritis. All PSACH, and the largest proportion of MED, result from mutations in cartilage oligomeric matrix protein (COMP). The first mutations in COMP were identified in 1995 in patients with both PSACH and MED and subsequently there has been over 30 publications describing COMP mutations in at least 250 PSACH–MED patients. However, despite these discoveries, a methodical analysis of the relationship between COMP mutations and phenotypes has not been undertaken. In particular, there has, to date, been little correlation between the type and location of a COMP mutation and the resulting phenotype of PSACH or MED. To determine if genotype to phenotype correlations could be derived for COMP, we collated 300 COMP mutations, including 25 recently identified novel mutations. The results of this analysis demonstrate that mutations in specific residues and/or regions of the type III repeats of COMP are significantly associated with either PSACH or MED. This newly derived genotype to phenotype correlation may aid in determining the prognosis of PSACH and MED, including the prediction of disease severity, and in the long term guide genetic counselling and contribute to the clinical management of patients with these diseases.
doi:10.1038/ejhg.2014.30
PMCID: PMC4051597  PMID: 24595329
10.  Managing clinically significant findings in research: the UK10K example 
European Journal of Human Genetics  2014;22(9):1100-1104.
Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs.
doi:10.1038/ejhg.2013.290
PMCID: PMC4026295  PMID: 24424120
incidental findings; ethics; sequencing; research; consortia; management pathway
11.  A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array 
Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.
doi:10.1038/ejhg.2012.242
PMCID: PMC3682876  PMID: 23188048
aPTT; coagulation; genotype; SNP
12.  Influence of the cystathionine β-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations 
A high homocysteine, low folate phenotype is a feature of many diseases. The effect of the cystathionine β-synthase (CBS) 844ins68 polymorphism on homocysteine and folate concentrations was examined alone and in the context of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in a Northwestern European male population. The MTHFR 677TT genotype is known to be associated with increased homocysteine and decreased folate relative to CT heterozygotes and CC homozygotes in this and other populations. MTHFR 677TT homozygotes who were also CBS 844ins68 carriers had homocysteine and folate concentrations similar to those of individuals with the MTHFR 677CT and CC genotypes. Homocysteine levels in MTHFR 677TT subjects carrying the CBS 844ins68 allele were 24.1% lower than in non-carriers (6.66 vs 8.77 μmol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele ‘normalizes’ homocysteine and folate levels in MTHFR 677TT individuals.
doi:10.1038/ejhg.2008.69
PMCID: PMC4051220  PMID: 18398434
folate; homocysteine; hyperhomocysteinemia; MTHFR; CBS
13.  A unifying framework for robust association testing, estimation, and genetic model selection using the generalized linear model 
European journal of human genetics : EJHG  2013;21(12):10.1038/ejhg.2013.62.
The analysis of genome-wide genetic association studies generally starts with univariate statistical tests of each single nucleotide polymorphism. The standard approach is the Cochran-Armitage trend test or its logistic regression equivalent although this approach can lose considerable power if the underlying genetic model is not additive. An alternative is the MAX test which is robust against the three basic modes of inheritance. Here, the asymptotic distribution of the MAX test is derived using the generalized linear model together with the Delta method and multiple contrasts. The approach is applicable to binary, quantitative, and survival traits. It may be used for unrelated individuals, family-based studies, and matched pairs. The approach provides point and interval effect estimates and allows selecting the most plausible genetic model using the minimum p-value. R code is provided. A Monte-Carlo simulation study shows that the asymptotic MAX test framework meets type I error levels well, has good power and good model selection properties for minor allele frequencies ≥0.3. Pearson’s chi-square test is superior for lower minor allele frequencies with low frequencies for the rare homozygous genotype. In these cases, the model selection procedure should be used with caution. The use of the MAX test is illustrated by re-analyzing findings from 7 genome-wide association studies including case-control, matched pairs, and quantitative trait data.
doi:10.1038/ejhg.2013.62
PMCID: PMC3820468  PMID: 23572026
Family-based association; genetic association; genome-wide association; indirect mapping; MAX test
14.  Homozygosity analysis in amyotrophic lateral sclerosis 
European journal of human genetics : EJHG  2013;21(12):10.1038/ejhg.2013.59.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognized dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. 620 ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2Mb were identified, and 3568 rare segments remained after filtering “common” segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, p=0.05). 2017 ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (p=1×10−5), a greater proportion of cases harboured homozygosity (p=2×10−5), a longer average length of segment (p=1×10−5), a longer total genome coverage (p=1×10−5), and a higher rate of these segments overlapped with RefSeq gene regions (p=1×10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9Mb to 4.8Mb, and chromosome 5 in the 65Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; genetics; recessive
15.  Genetic perspectives on the origin of clicks in Bantu languages from southwestern Zambia 
Some Bantu languages spoken in southwestern Zambia and neighboring regions of Botswana, Namibia, and Angola are characterized by the presence of click consonants, whereas their closest linguistic relatives lack such clicks. As clicks are a typical feature not of the Bantu language family, but of Khoisan languages, it is highly probable that the Bantu languages in question borrowed the clicks from Khoisan languages. In this paper, we combine complete mitochondrial genome sequences from a representative sample of populations from the Western Province of Zambia speaking Bantu languages with and without clicks, with fine-scaled analyses of Y-chromosomal single nucleotide polymorphisms and short tandem repeats to investigate the prehistoric contact that led to this borrowing of click consonants. Our results reveal complex population-specific histories, with female-biased admixture from Khoisan-speaking groups associated with the incorporation of click sounds in one Bantu-speaking population, while concomitant levels of potential Khoisan admixture did not result in sound change in another. Furthermore, the lack of sequence sharing between the Bantu-speaking groups from southwestern Zambia investigated here and extant Khoisan populations provides an indication that there must have been genetic substructure in the Khoisan-speaking indigenous groups of southern Africa that did not survive until the present or has been substantially reduced.
doi:10.1038/ejhg.2012.192
PMCID: PMC3598317  PMID: 22929022
Zambia; Bantu; Khoisan; mtDNA; Y chromosome; clicks
16.  Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach 
A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.
doi:10.1038/ejhg.2008.13
PMCID: PMC3905962  PMID: 18285836
BRCA1; BRIP1; CtIP; hereditary breast cancer; missense variants
17.  A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array 
Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50,000 single nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women’s Heart and Health Study. We confirm associations with aPTT at the F12/GRK6 and KNG1/HRG loci, and identify novel SNPs at the ABO locus and novel locus KLKB1/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/SLC19A2 regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.
doi:10.1038/ejhg.2012.242
PMCID: PMC3682876  PMID: 23188048
aPTT; coagulation; genotype; SNP
18.  Engagement with genetic discrimination: concerns and experiences in the context of Huntington disease 
It has been over 20 years since the inception of predictive testing for Huntington disease (HD), yet the social implications of knowing one's genetic risk for HD have not been fully explored. Genetic discrimination (GD) is a potential risk associated with predictive testing. Although anecdotal reports of GD have been documented, there is a paucity of research on the nature and experiences of GD in the context of HD. The purpose of this study was to describe the concerns and experiences of GD in the HD community. Semistructured interviews were conducted with 45 genetically tested and 10 untested individuals and analyzed using grounded theory methods. Our findings demonstrate that a majority of individuals were concerned about (37/55) and experienced GD (32/55) across a variety of contexts that extend beyond the traditionally examined contexts of insurance and employment to include family, social, government, and health-care domains. We describe a process of engagement with GD in which individuals formed meaningful interpretations of GD and personalized its risk and consequences in their lives. Our findings provide an insight into some of the specific processes and factors influencing engagement with GD. These results help identify areas where more education and support is needed and provide direction to genetic professionals supporting their clients as they confront issues of GD and genetic testing.
doi:10.1038/sj.ejhg.5201937
PMCID: PMC3806301  PMID: 17957229
genetic discrimination; Huntington disease; predictive testing; stigma
19.  Genetic perspectives on the origin of clicks in Bantu languages from southwestern Zambia 
Some Bantu languages spoken in southwestern Zambia and neighboring regions of Botswana, Namibia, and Angola are characterized by the presence of click consonants, whereas their closest linguistic relatives lack such clicks. As clicks are a typical feature not of the Bantu language family, but of Khoisan languages, it is highly probable that the Bantu languages in question borrowed the clicks from Khoisan languages. In this paper, we combine complete mitochondrial genome sequences from a representative sample of populations from the Western Province of Zambia speaking Bantu languages with and without clicks, with fine-scaled analyses of Y-chromosomal single nucleotide polymorphisms and short tandem repeats to investigate the prehistoric contact that led to this borrowing of click consonants. Our results reveal complex population-specific histories, with female-biased admixture from Khoisan-speaking groups associated with the incorporation of click sounds in one Bantu-speaking population, while concomitant levels of potential Khoisan admixture did not result in sound change in another. Furthermore, the lack of sequence sharing between the Bantu-speaking groups from southwestern Zambia investigated here and extant Khoisan populations provides an indication that there must have been genetic substructure in the Khoisan-speaking indigenous groups of southern Africa that did not survive until the present or has been substantially reduced.
doi:10.1038/ejhg.2012.192
PMCID: PMC3598317  PMID: 22929022
Zambia; Bantu; Khoisan; mtDNA; Y chromosome; clicks
20.  Variable Selection in Logistic Regression for Detecting SNP-SNP Interactions: the Rheumatoid Arthritis Example 
Summary
Many complex disease traits are observed to be associated with single nucleotide polymorphism (SNP) interactions. In testing small-scale SNP-SNP interactions, variable selection procedures in logistic regressions are commonly used. The empirical evidence of variable selection for testing interactions in logistic regressions is limited. This simulation study was designed to compare nine variable selection procedures in logistic regressions for testing SNP-SNP interactions. Data on 10 SNPs were simulated for 400 and 1000 subjects (case/control ratio=1). The simulated model included one main effect and two 2-way interactions. The variable selection procedures included automatic selection (stepwise, forward and backward), common 2-step selection, AIC- and BIC-based selection. The hierarchical rule effect, in which all main effects and lower order terms of the highest-order interaction term are included in the model regardless of their statistical significance, was also examined. We found that the stepwise variable selection without the hierarchical rule which had reasonably high authentic (true positive) proportion and low noise (false positive) proportion, is a better method compared to other variable selection procedures. The procedure without the hierarchical rule requires fewer terms in testing interactions, so it can accommodate more SNPs than the procedure with the hierarchical rule. For testing interactions, the procedures without the hierarchical rule had higher authentic proportion and lower noise proportion compared with ones with the hierarchical rule. These variable selection procedures were also applied and compared in a rheumatoid arthritis study.
doi:10.1038/sj.ejhg.5202010
PMCID: PMC3786179  PMID: 18231122
single nucleotide polymorphisms; gene interaction; logistic model; variable selection
21.  Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers 
FMR1 premutations are known to be associated with premature ovarian failure (POF), but the underlying mechanism is unknown. We present evidence for a nonlinear association between menopause age and premutation size suggesting that premutations in the mid-size range are at greatest risk for POF, while larger premutations are at lower risk.
doi:10.1038/sj.ejhg.5201510
PMCID: PMC3725422  PMID: 16251893
FMR1; permutation; premature ovarian failure
22.  Reproductive and menstrual history of females with fragile X expansions 
FRAXA premutations have been associated with premature ovarian failure (POF) or menopause before the age of 40. We have studied women in families ascertained because of a mentally retarded full mutation relative and determined their age of menopause, serum hormone levels in premenopausal individuals and the outcome of any pregnancies. Survival analysis was used as a measure of menopause and demonstrated a significant decrease in age of menopause in premutation carriers compared with their full mutation carrier and normal relatives. Serum FSH was also raised in premutation carriers, although oestradiol, inhibin A and inhibin B were not significantly different. However, we did not find an excess of dizygous twins or pregnancy loss/trisomies, both of which are associated with aging ovaries. Thus premutation carriers as a group have an earlier menopause and raised serum FSH but do not appear to manifest other features of an aging ovary.
doi:10.1038/sj.ejhg.5200451
PMCID: PMC3725540  PMID: 10854106
Fragile X; premutation; premature ovarian failure
23.  Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes 
The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.
doi:10.1038/ejhg.2011.234
PMCID: PMC3330215  PMID: 22258527
Waardenburg syndrome; Tietz syndrome; MITF; freckles; pigmentation
24.  Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother 
The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5–30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5–30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28–30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40–29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.
doi:10.1038/ejhg.2011.244
PMCID: PMC3330222  PMID: 22234155
duplication 16p11.2p12.2; deletion 16p11.2; autism; intellectual disability; SH2B1; SNP array
25.  Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother 
The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5–30.1 Mb) are associated with autism, intellectual disability and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5–30.1 Mb) has been described in six individuals with intellectual disability, while apparently reciprocal duplications, studied by standard cytogenetic and FISH techniques, have been reported in three patients with autism spectrum disorders. Here we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28–30.23 Mb) characterized by SNP array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe intellectual disability, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild intellectual disability, early onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40–29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early onset obesity and in individuals with neurodevelopmental disorders, associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.
doi:10.1038/ejhg.2011.244
PMCID: PMC3330222  PMID: 22234155
Abnormalities, Multiple; genetics; Adolescent; Adult; Autistic Disorder; genetics; Chromosomes, Human, Pair 16; genetics; DNA Copy Number Variations; Gene Duplication; Humans; Male; Phenotype; Sequence Deletion; Siblings; Twins, Monozygotic; genetics; duplication 16p11.2p12.2; deletion 16p11.2; autism; intellectual disability; SH2B1; SNP array

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