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OBJECTIVE Israel is one of the first countries to incorporate chromosomal microarray analysis into routine prenatal care. We explored attitudes of Israeli healthcare professionals (HCPs) towards the disclosure of challenging findings: variants of uncertain clinical significance (VUS), susceptibility loci (SL) for neurodevelopmental disorders and variants associated with adult-onset (AO) conditions. Particularly, we sought their views on providing parental choice regarding the disclosure of these findings. METHODS Twenty-nine in-depth interviews were conducted with genetic counselors (n = 19), medical geneticists (n = 4), medical geneticists that are trained in and practice fetal medicine (n = 3), and fetal medicine experts (n = 3). RESULTS Most participants (n = 24) supported parental choice regarding uncertain genetic information. Engaging parents in disclosure decisions allows avoidance from potentially anxiety-provoking information, practicing parental autonomy, and better preparation in cases where uncertain findings are identified. HCPs believed that given appropriate preparation, parents can make informed decisions. Four participants believed that disclosure should be based on professional judgment and one supported full-disclosure. Unlike VUS or SL, all interviewees agreed that in cases of medically actionable AO conditions, the benefit of disclosure outweighs the damage. CONCLUSION HCPs attitudes are largely in-line with the Israeli practice of involving parents in disclosure decisions regarding uncertain information. This may mitigate disclosure dilemmas and allow personalized disclosure based on parents' views.

Summary Pyrenophora teres f. teres and P. teres f. maculata are significant pathogens that cause net blotch of barley. An increased number of loci involved in P. teres resistance or susceptibility responses of barley as well as interacting P. teres virulence effector loci have recently been identified through biparental and association mapping studies of both the pathogen and host. Characterization of the resistance/susceptibility loci in the host and the interacting effector loci in the pathogen will provide a path for targeted gene validation for better‐informed release of resistant barley cultivars. This review assembles concise consensus maps for all loci published for both the host and pathogen, providing a useful resource for the community to be used in pathogen characterization and barley breeding for resistance to both forms of P. teres., Pyrenophora teres causes net blotch of barley. Here we review the latest progress on host resistance and pathogen virulence, providing a valuable resource for the barley net blotch research community.

__Background:__ Whole genome array testing not only provides an increased diagnostic yield of pathogenic causative findings, but it may also reveal so called susceptibility loci (SL) for neurodevelopmental disorders. The goal of this study was to evaluate the pregnancy outcomes in SL cases and to establish a protocol for pregnancy management, follow-up and additional investigations. __Methods:__ Fifty seven cases were evaluated: 34 with and 23 without ultrasound anomalies at referral. Each pregnant couple received pretest counseling and extensive posttest genetic counseling. __Results:__ After diagnosis of SL, parental testing and an additional ultrasound examination were offered. The severity of the ultrasound anomalies and not the diagnosis of SL was the most important factor contributing to the decision on pregnancy continuation. In the majority of cases with milder or no ultrasound anomalies, the pregnancy was continued and a normal outcome after birth was observed. __Conclusions:__ The diagnosis of a SL did not seem to be a reason for termination of pregnancy. Most patients were able to cope with the uncertainty and were interested in both prenatal and postnatal actionability of SL. Long-term follow-up is crucial to assess the actual risks for neurodevelopmental disorders, especially in families with unremarkable history.

The term "fetal alcohol spectrum disorders" (FASD) defines the full range of ethanol (EtOH)-induced birth defects. Numerous variables influence the phenotypic outcomes of embryonic EtOH exposure. Among these variables, genetics appears to play an important role, yet our understanding of the genetic predisposition to FASD is still in its infancy. We review the current literature that relates to the genetics of FASD susceptibility and gene-EtOH interactions. Where possible, we comment on potential mechanisms of reported gene-EtOH interactions. Early indications of genetic sensitivity to FASD came from human and animal studies using twins or inbred strains, respectively. These analyses prompted searches for susceptibility loci involved in EtOH metabolism and analyses of candidate loci, based on phenotypes observed in FASD. More recently, genetic screens in animal models have provided an additional insight into the genetics of FASD. Understanding FASD requires that we understand the many factors influencing phenotypic outcome following embryonic EtOH exposure. We are gaining ground on understanding some of the genetics behind FASD, yet much work remains to be carried out. Coordinated analyses using human patients and animal models are likely to be highly fruitful in uncovering the genetics behind FASD.

BACKGROUND Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of

Aim The objective of the present meta-analysis was to investigate whether or not cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) polymorphisms are associated with ankylosing spondylitis (AS) susceptibility. Methods A systematic search was conducted from the PubMed, ENBASE, and Springer link database up to April 2014. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association between CTLA-4 (+49 A/G) and AS risk. A subgroup analysis based on geographic region and a sensitivity analysis were also conducted. Results Five studies were eligible for meta-analysis, including 918 cases and 845 controls. The results showed that no significant association was found between AS and CTLA-4 (+49 A/G) for the additive model (G vs. A), dominant model (GG + AG vs. AA), co-dominant model (GG vs. AA, AG vs. AA) and recessive model (GG vs. AG + AA). The OR was 1.09 (95% CI, 0.87–1.38), 1.16 (95% CI, 0.89–1.51), 1.05 (95% CI, 0.75–1.46), 1.15 (95% CI, 0.86–1.52) and 0.99 (95% CI, 0.79–1.23), respectively. Although subgroup analysis demonstrated no association between CTLA-4 (+49 A/G) polymorphisms and susceptibility to AS in Europe and Taiwan, an association was found in Iran through both the co-dominant and dominant models. Exclusion of any individual study did not alter the significance of the final outcome, excepting the result by omitting the study by Huang et al. Conclusions The present results suggest that the CTLA-4 may not be a major susceptibility locus in humans with AS. The relationship between them may be affected by different geographic populations.

Genomic array detects more pathogenic chromosome aberrations than conventional karyotyping (CK), including genetic variants associated with a susceptibility for neurodevelopmental disorders; susceptibility loci (SL). Consensus regarding the scope of invasive prenatal diagnosis (PND) pregnant couples should be offered is lacking. This study examined pregnant couples' preferences, doubts and satisfaction regarding the scope of invasive PND. Eighty-two couples choosing prenatal screening (PNS) and 59 couples choosing invasive PND were offered a choice between 5 (comparable to CK) and 0.5 Mb resolution array analysis outcomes, the latter with or without reporting SL. A pre-test self-report questionnaire and post-test telephone interview assessed their choices in-depth. Actual (PND) and hypothetical (PNS) choices differed significantly (p

Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genome-wide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

Background: Although genome-wide association studies have identified several susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations around the world, the role of most loci is unknown in the highly heterogeneous Brazilian population. Methods: To determine the association of 7 markers that showed genome-wide significant association in Brazilians with NSCL/P, we conducted a structured association study conditioned upon the individual ancestry proportions to evaluate markers at 1p36 (rs742071), 2p21 (rs7590268), 3p11.1 (rs7632427), 8q21.3 (rs12543318), 13q31.1 (rs8001641), 15q22.2 (rs1873147), and 17q22 (rs227731) in 505 patients with NSCL/P and 594 healthy controls recruited from 2 different geographical regions of Brazil. The polymorphisms were genotyped by TaqMan 5′-exonuclease allelic discrimination assay, and each sample was independently typed for 40 biallelic short insertion/deletion markers to characterize the genomic ancestry. Results: After Bonferroni correction for multiple tests, significant associations with NSCL/P were observed for rs742071, rs1873147, and rs227731. However, the frequency of the risk alleles varied between the geographical regions, according to the proportions of European and African genomic ancestry. The group enriched by European ancestry showed significant association with rs227731 (p = 0.001), whereas the group with high African ancestry was significantly associated with rs1873147 polymorphism (p = 0.005). The significant association with rs742071 was only detected in the combined sample (p = 0.005). Conclusion: The findings of the present study revealed the associations of 1p36 (rs742071), 15q22 (rs1873147), and 17p22 (rs227731) with NSCL/P in the Brazilian population, and further confirmed that the genetic heterogeneity of NSCL/P may be related to the different ethnic background of the affected individuals. Birth Defects Research (Part A) 100:36–42, 2014. © 2013 Wiley Periodicals, Inc.

Objective—Many confirmed genetic loci for obesity are expressed in regions of the brain that regulate energy intake and reward-seeking behavior. Whether these loci contribute to the development of specific eating behaviors has not been investigated. We examined the relationship between a genetic susceptibility to obesity and cognitive restraint, uncontrolled and emotional eating. Design and Methods—Eating behavior and body mass index (BMI) were determined by questionnaires for 1471 men and 2381 women from two U.S cohorts. Genotypes were extracted from genome-wide scans and a genetic-risk score (GRS) derived from 32 obesity-loci was calculated. Results—The GRS was positively associated with emotional and uncontrolled eating(P

Distal 15q25.2 microdeletions have recently been reported as a copy number variation (CNV) locus for neurodevelopmental and neuropsychiatric disorders with variable outcome. In addition, more proximal microdeletions of 15q25.2 have been described as a susceptibility locus for cognitive deficits, congenital diaphragmatic hernia (CDH), and Diamond-Blackfan anaemia (DBA). We describe two patients with 15q25.2 deletion, one with the more distal deletion and the other with a deletion overlapping both the distal and proximal 15q25.2 deletions and compare them to the 18 so far reported patients with 15q25.2 deletions. We provide a characterization of the 15q25.2 microdeletions and contribute to the genotype-phenotype delineation for these two novel microdeletion syndromes.

A Scandinavian multi-centre study replicates 11 susceptibility loci from genome-wide association studies in Parkinson's disease

Type 2 diabetes (T2D) has become a leading health problem throughout the world. It is caused by environmental and genetic factors, as well as interactions between the two. However, until very recently, the T2D susceptibility genes have been poorly understood. During the past 5 years, with the advent of genome-wide association studies (GWAS), a total of 58 T2D susceptibility loci have been associated with T2D risk at a genome-wide significance level (P < 5 × 10(-8) ), with evidence showing that most of these genetic variants influence pancreatic β-cell function. Most novel T2D susceptibility loci were identified through GWAS in European populations and later confirmed in other ethnic groups. Although the recent discovery of novel T2D susceptibility loci has contributed substantially to our understanding of the pathophysiology of the disease, the clinical utility of these loci in disease prediction and prognosis is limited. More studies using multi-ethnic meta-analysis, gene-environment interaction analysis, sequencing analysis, epigenetic analysis, and functional experiments are needed to identify new susceptibility T2D loci and causal variants, and to establish biological mechanisms.

In recent decades, the prevalence of type 2 diabetes in China has increased significantly, underscoring the importance of investigating the etiological mechanisms, including genetic determinants, of the disease in Chinese populations. Numerous loci conferring susceptibility to type 2 diabetes (T2D) have been identified worldwide, with most having been identified in European populations. In terms of ethnic heterogeneity in pathogenesis as well as disease predisposition, it is imperative to explore the specific genetic architecture of T2D in Han Chinese. Replication studies of European-derived susceptibility loci have been performed, validating 11 of 32 loci in Chinese populations. Genetic investigations into heritable traits related to glucose metabolism are expected to provide new insights into the pathogenesis of T2D, and such studies have already inferred some new susceptibility loci. Other than replication studies of European-derived loci, efforts have been made to identify specific susceptibility loci in Chinese populations using methods such as genome-wide association studies. These efforts have identified additional new loci for the disease. Genetic studies can facilitate the prediction of risk for T2D and also promote individualized anti-diabetic treatment. Despite many advances in the field of risk prediction and pharmacogenetics, the pace of clinical application of these findings is rather slow. As a result, more studies into the practical utility of these findings remain necessary.

Aims. Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially att ...

Background: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer. Aims: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations. Materials and methods: The rs8034191 SNP genotyped in 551 children from the environment and childhood asthma (ECA) birth cohort study in Oslo, Norway, and in 516 families from six European centers [the Genetics of Asthma International Network (GAIN) study] was tested for genotypic or allelic associations to current or history of asthma, allergic sensitization (= one positive skin prick tests), bronchial hyperresponsiveness (BHR), and lung function (FEV1% of predicted and FEV1/FVC ratio over/ below the 5th percentile). Results: Although the TT and CT genotypes at SNP rs 8034191 were overall significantly associated with BHR (OR = 3.9, 95% CI 1.510.0, p = 0.005), stratified analyses according to exposure to maternal smoking in-utero or indoor smoking at 10 yrs of age showed significant association (OR = 4.4, 95% CI 1.512.6, p = 0.006 and OR 5.6, 95% CI 1.718.5, p = 0.004, respectively) only in the non-exposed and not in exposed children. The SNPBHR association was replicated in the non-tobacco-smoke-exposed subjects in one of the GAIN centers (BHR associated with the T allele (p = 0.034)), but not in the collated GAIN populations. Asthma, allergic sensitization, and lung function were not associated with the rs8034191 alleles. Conclusion: An interaction between tobacco smoke exposure and a CHRNA3/5 polymorphism was found for BHR in children, but CHRNA3/5 was not associated with asthma or lung function.

Large-scale meta-analyses of genome-wide association scans (GWAS) have been successful in discovering common risk variants with modest and small effects. The detection of lower frequency signals will undoubtedly require concerted efforts of at least similar scale. We investigate the sample size-dictated power limits of GWAS meta-analyses, in the presence and absence of modest levels of heterogeneity and across a range of different allelic architectures. We find that data combination through large-scale collaboration is vital in the quest for complex trait susceptibility loci, but that effect size heterogeneity across meta-analyzed studies drawn from similar populations does not appear to have a profound effect on sample size requirements.

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene Rahman et al. (2007) Nature Genetics 39: 165–167 A common coding variant in CASP8 is associated with breast cancer risk Cox et al. (2007) Nature Genetics 39: 352–358 A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer Hunter et al. (2007) Nature Genetics 39: 870–874 Genome-wide association study identifies novel breast cancer susceptibility loci Easton et al. (2007) Nature 447: 1087–1093 Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer Stacey et al. (2007) Nature Genetics 39: 865–869

Schizophrenia is a complex psychiatric disorder, likely to be caused in part by multiple genes. In this study, linkage analyses were performed to identify chromosomal regions most likely to be associated with schizophrenia and psychosis in multiplex families of Mexican and Central American origin. Four hundred and fifty-nine individuals from 99 families, containing at least two siblings with hospital diagnoses of schizophrenia or schizoaffective disorder, were genotyped. Four hundred and four microsatellite markers were genotyped for all individuals and multipoint non-parametric linkage analyses were performed using broad (any psychosis) and narrow (schizophrenia and schizoaffective disorder) models. Under the broad model, three chromosomal regions (1pter-p36, 5q35, and 18p11) exhibited evidence of linkage with non-parametric lod (NPL) scores greater than 2.7 (equivalent to empirical P values of less than 0.001) with the peak multipoint NPL = 3.42 (empirical P value = 0.00003), meeting genomewide evidence for significant linkage in the 1pter-p36 region. Under the narrow model, the same three loci showed (non-significant) evidence of linkage. These linkage findings (1pter-p36, 18p11, and 5q35) highlight where genes for psychosis and schizophrenia are most likely to be found in persons of Mexican and Central American ancestry, and correspond to recent linkages of schizophrenia or psychosis in other populations which were formed in part from emigrants from the Spanish empire of the 15th and 16th centuries. © 2006 Wiley-Liss, Inc.

Supported by grants from the NIH (5P01-AI-083194 to Drs. Lessard, Rasmussen, Gaffney, Alarcon-Riquelme, Criswell, Jacob, Kimberly, Vyse, Harley, Sivils, Langefeld, and Tsao; 5P01-AR-049084 to Drs. Kimberly and Langefeld; and R01-AR-043814 and R21-AR-065626 to Dr. Tsao), the Oklahoma Medical Research Foundation (to Drs. Lessard, Gaffney, and Sivils), the Alliance for Lupus Research (to Drs. Criswell and Tsao), and the Wake Forest School of Medicine Center for Public Health Genomics (to Dr. Langefeld). Dr. Criswell is recipient of a Kirkland Scholar Award. Sample collection and phenotyping of the subjects utilized in this study was funded by the Ministry for Health and Welfare, Republic of Korea (Korea Healthcare Technology R&D Project grant HI13C2124 to Dr. Bae, and HI13C1754 to Dr. Song). The out-of-study Korean control data were provided by the Korean Biobank Project, which is supported by the Korea Centers for Disease Control and Prevention at the Korea National Institute of Health.

To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.

We have witnessed great success in the identification of new type 2 diabetes susceptibility loci through genome‐wide association (GWA) analysis in the past 5 years. The number of loci robustly implicated in type 2 diabetes risk; that is, those that have attained a genome‐wide significance level (P 50 today. As these GWA studies were carried out almost exclusively in European‐descent populations, studies in non‐European populations will allow us to assess the relevance of the findings to other ethnic groups. To address this point, a consortium‐based GWA meta‐analysis of type 2 diabetes was recently carried out in East Asians with a multistage study design (involving >25,000 cases and >29,000 controls in total)1; eight new loci were confirmed to significantly associate with type 2 diabetes. This large‐scale GWA meta‐analysis was principally carried out in the Asian Genetic Epidemiology Network (AGEN), in which our group participated together with investigators from Japan, Korea, China, Taiwan, Singapore and the USA.

Susceptibility to N-methyl-N-nitrosourea (MNU)-induced lymphomas is a multigenic trait. We previously mapped a resistance locus (Tlag1) to mouse chromosome 7 in genetic crosses of sensitive AKR with resistant C57L mice. Analysis of the MNU sensitivity of AKXL recombinant inbred strains that are homozygous for the AKR allele of Tlag1 suggested that at least two additional tumor susceptibility loci segregate in these crosses. A second susceptibility locus (Tlag2) now has been mapped to chromosome 4. Only those mice that inherited the susceptibility alleles at both Tlag1 and Tlag2 were sensitive to MNU induction of thymic lymphomas, suggesting that these two loci interact. Chromosome 4 has been associated with susceptibility to hematopoietic tumor development in several mouse models, suggesting that one or more genes mapping to this chromosome are important in lymphomagenesis in general.

The objectives of this study were 1 to assess in a population-wide study the genetic component of hip OA in Iceland leading to total joint replacement (THR) 2 to describe a large kinship with inherited hip OA and its associated susceptibility locus

SUMMARY Initial neurobiological and genetic evi-dence of inheritance of a physiologicalabnormality related to schizophreniahas been obtained, that implicates thea7 nicotinic receptor gene. Bilineal in-heritance may be associated with moresevere, earlier onset illness. Replicationof these findings, identification of themolecular abnormality in the gene, anddetermination of the full role of the ab-normality in psychotic illnesses are nec-essary next steps to determine the roleof this gene in the pathogenesis ofschizophrenia. REFERENCES Adams CE, Stevens KE. 1998. Inhibition of nitricoxide synthetase disrupts inhibitory gatingof auditory responses in rat hippocampus. JPharmacol Exp Ther 287:760–765.Adler LE, Pachtman E, Franks R, Pecevich M,Waldo MC, Freedman R. 1982. Neuro-physiological evidence for a deficit in in-hibitory mechanisms involved in sensorygating in schizophrenia. Biol Psychiatry 17:639–654.Adler LE, Gerhardt GA, Franks R, Baker N,Nagamoto H, Drebing C, Freedman R.1989. Sensory physiology and catechol-amines in schizophrenia and mania. Psychi-atr Res 31:297–309.Adler LE, Hoffer LJ, Griffith J, Waldo M, Freed-man R. 1992. Normalization by nicotine ofdeficient auditory sensory gating in the rela-tives of schizophrenics. Biol Psychiatr 32:607–616.Adler LE, Hoffer LD, Wiser A, Freedman R.1993. Normalization of auditory physiologyby cigarette smoking in schizophrenic pa-tients. Am J Psychiatr 150:1856–1861.Andreasen NC, Paradiso S, O’Leary DS. 1998.“Cognitive dysmetria” as an integrativetheory of schizophrenia: a dysfunction incortical subcortical-cerebellar circuitry?Schizophr Bull 24:203–218.Arolt V, Lencer R, Nolte A, Muller-Myhsok B,Purmann S, Schurmann M, Leutelt J, Pin-now M, Schwinger E. 1996. Eye trackingdysfunction is a putative phenotypic suscep-tibility marker of schizophrenia and maps toa locus on chromosome 6p in families withmultiple occurrence of the disease. Am JMed Genet 67:564–579.Baker NJ, Staunton M, Adler LE, Gerhardt GA,Drebing C, Waldo M, Nagamoto H,Freedman R. 1990. Sensory gating deficitsin psychiatric inpatients: Relation to cate-cholamine metabolites in different diagnos-tic groups. Biol Psychiatr 27:519–528.Berrettini WH, Ferraro TN, Goldin LR, Detera-Wadleigh SD, Choi H, Muniec D, GuroffJJ, Kazuba DM, Nurnberger JI Jr, HsiehWT, Hoehe MR, Gershon ES. 1997. Alinkage study of bipolar illness. Arch GenPsychiatry 54:27–35.Bickford PC, Luntz-Leybman V, Freedman R.1993. Auditory sensory gating in the rathippocampus: modulation by brainstem ac-tivity. Brain Res 607:33–38.Bickford-Wimer PC, Nagamoto H, Johnson R,Adler LE, Egan M, Rose GM, FreedmanR. 1990. Auditory sensory gating in hippo-campal neurons: a model system in the rat.Biol Psychiatr 27:183–192.Bickford PC, Wear KD. 1995. Restoration ofsensory gating of auditory evoked responseby nicotine in fimbria-fornix lesioned rats.Brain Res 705:235–240.Blouin JL, Dombroski BA, Nath SK, LasseterVK, Wolyniec PS, Nestadt G, ThornquistM, Ullrich G, Mcgrath J, Kasch L, LamaczM, Thomas MG, Gehrig C, RadhakrishnaU, Snyder SE, Balk KG, Neufeld K, SwartzKL, Demarchi N, Papadimitriou GN,Dikeos DG, Stefanis CN, Chakravarti A,Childs B, Housman DE, Pulver AE. 1998.Schizophrenia susceptibility loci on chro-mosome 13q31 and 8p21. Nature Genet 20:70–73.Borecki IB, Rao DC, Yaouanq J, Lalouel JM.1990. Serum ferritin as a marker of affectionfor genetic hemochromatosis. HumanHered 40:159–166.Boutros NN, Zouridakis G, Overall J. 1991.Replication and extension of P50 findingsin schizophrenia. Clin Electroencephalogr22:40–45.Breese CR, Adams C, Logel J, Drebing C, Roll-ins Y, Barnhart M, Sullivan B, DeMastersBK, Freedman R, Leonard S. 1997. Com-parison of the regional expression of nico-tinic acetylcholine receptor a7 mRNA and[

Cleft lip with or without cleft palate (CL/P) is one of the mostcommonhumanbirthdefects.CL/Pmayoccuraspartofacomplexmalformation syndrome or, as is more commonly the case, as anonsyndromic malformation. In European populations non-syndromic cleft lip with or without cleft palate (NSCL/P) has abirth prevalence of 1/700–1/1,000. NSCL/P has a multifactorialetiology resulting from interactions between multiple genetic andenvironmentalfactors.Nonsyndromiccleftpalateonly(NSCPO)isthe second most common form of nonsyndromic clefting, with aprevalence of 1/2,000 in most European populations. AlthoughNSCL/P and NSCPO are generally considered to be develop-mentally and genetically distinct entities, there is evidence thatthey may have an etiological overlap [Kondo et al., 2002; Sivertsenet al., 2008].The identification of susceptibility genes for NSCL/P has beenthe subject of extensive research. Of the many candidate genesinvestigated, however, only the IRF6 gene has shown a convincingdegreeofconsistencyacrossstudies[Zuccheroetal.,2004;Rahimovet al., 2008]. The first genome-wide association scan (GWAS)recently reported a new major susceptibility locus at chromosome8q24.21,with the strongestassociationsignal having been observedfor rs987525 (P¼3.34 10

Genome searches have been performed for many complex traits, and in some cases several searches have been performed in a single disease. Replication of significant results is rare, and a systematic method of reviewing results from a number of searches is needed. A method for meta-analysis is presented which provides a systematic descriptive overview of the separate analyses while dealing with some of the problems specific to meta-analysis of genome searches. The results of two separate meta-analyses correctly indicate the presence of susceptibility loci on chromosomes 1, 3, and 5 in the GAW11 Problem 2 data.

A combined linkage analysis was performed on chromosome 18 data and produced modest evidence in three of four data sets for linkage of a susceptibility locus for bipolar disorder to markers on chromosome 18p. All data sets showed a preponderance of females among affected individuals. When this was taken into account, no convincing evidence was obtained for excess transmission from mothers compared to fathers. In addition, there was no evidence for differences in the proportions of affected offspring from affected fathers and mothers. We conclude that these combined data do not support previous suggestions of a maternal effect on transmission of bipolar affective disorder.

The presence of a susceptibility locus for bipolar disorder on chromosome 5p near the dopamine transporter gene has been suggested. We examined 52 bipolar families for linkage to two markers in this region under both dominant and recessive models of inheritance. The purpose of the analyses was to determine the mode of inheritance of this purported bipolar locus. We also ran sensitivity analyses to confirm the reliability of the linkage results. Our results suggest that a bipolar locus inherited in an autosomal dominant fashion may be linked to this region in a subset of families.

Efforts to map susceptibility loci for complex human diseases frequently result in weak evidence for linkage, followed by failures to convincingly replicate. If a disease locus influences both affection status (AF) and a quantitative trait, a variant of the extreme discordant sib pair (EDSP) strategy may be used to judiciously sample families for a replication study. This approach was evaluated by conducting joint segregation and linkage analysis of four bivariate phenotypes, each comprising AF and one quantitative trait (Q2, Q3, Q4, Q5), and undertaking a genomic scan of the GAW10 Problem 2B data set. Suggestive evidence was found for linkage of AF/Q2 to marker D8G26 (lod = 1.63, chi 2 = 7.52, p = 3.05 x 10(-3)). Sets of 23 EDSP families were selected based on Q2 values that demarcated the bottom 1%, 2%, 5%, 10%, or 20% of the distribution. Highly significant evidence for linkage was found when the 1% or 2% cutoffs were used (lod > 4, chi 2 > 20, p < 4 x 10(-6)), but more than 1,000 families had to be screened. Significant evidence for linkage (lod = 3.24, chi 2 = 14.91, p = 5.63 x 10(-5)) was found in the EDSP sample obtained using a 5% cutoff: about 300 families had to be screened. Only suggestive evidence for linkage (lod = 1.65, chi 2 = 7.59, p = 2.93 x 10(-3)) was found in non-EDSP families. Use of EDSP sampling variants can permit convincing replications not otherwise obtainable in the genetic analysis of complex diseases.

We applied a new test statistic for linkage that removes the traditional assumption of equal female (theta f) and male (theta m) recombination fractions by testing Ho: theta f + theta m = 1 vs. HA: theta f + theta m < 1 to GAW10 Problem 1. Specifically we reanalyzed the reported possible linkage between a suggested susceptibility locus for bipolar affective disorder and marker D18S41 on chromosome 18 [Stine et al., 1995]. We used penetrance functions fitting the description of those used by Stine et al. [1995] assuming a continuous age-dependent logistic distribution. Maximum likelihood marker allele frequencies were estimated assuming Hardy-Weinberg equilibrium. Results from the traditional lod-score analyses do not strongly support the existence of linkage between the disease locus and marker D18S41. Similarly, the new test statistic for linkage failed to provide evidence in support of linkage. This was true whether dominant or recessive models of inheritance were assumed, and whether the analyses included all available pedigrees or were confined to paternally transmitted pedigrees. The appreciable difference found between our lod scores and those obtained by Stine et al. [1995] can be attributed to differences in the assumptions made regarding the age-dependent penetrance function, the marker allele frequencies, or both.

The identification of several putative susceptibility loci for nonsyndromic cleft lip with or without cleft palate (CL +/- P) has sparked a renewed interest in the genetics of this condition. However, prior to undertaking linkage studies for complex traits such as CL +/- P it is desirable to have some understanding of the number and nature of the loci involved in disease susceptibility. The ability to obtain valid estimates of these parameters is contingent on the availability of family data which are unbiased by factors that distort the true familial recurrence pattern. In an effort to obtain such data, 2 centralized data repositories (the Danish Central Person Registry and the Danish Facial Cleft Database), were linked and used to estimate the risks to first, second, and third-degree relatives of 3,073 CL +/- P probands born in Denmark from 1952 to 1987. Analyses of these data excluded single locus and additive multilocus inheritance of CL +/- P, and provided evidence that CL +/- P is most likely determined by the effects of multiple interacting loci. Under a multiplicative model, no single locus can account for more than a threefold increase in the risk to first-degree relatives of CL +/- P probands. These data provide further evidence that nonparametric linkage methods (ex. affected relative pair studies) are likely to represent a more realistic approach for identifying CL +/- P susceptibility loci, than are traditional pedigree-based methods. However, at least 100 and more realistically several hundred (300-500) affected sib pairs are likely to be required to detect linkage to CL +/- P susceptibility loci.

Two susceptibility genes, in linkage disequilibrium with alleles of the markers D1G31 and D5G23, have been identified for the disease in the simulated data set of Problem 1. Here we apply the MASC (marker association segregation chi-square) method to model the joint effect of these two genes, by testing two-locus models. The model we obtain, that is the most parsimonious and that best fits the data, corresponds to a direct involvement of the alleles D1G31-8 and D5G23-7, with a nonmultiplicative effect of the two alleles. This was indeed assumed in the true model used for simulating the data. ©1995 Wiley-Liss, Inc.

Fifteen pedigrees with a total of 75 cases of breast cancer, 10 of ovarian cancer and 53 of other cancers have been collected. Polymorphic markers on chromosome 17q have been screened to locate a putative breast-cancer gene using DNA from relevant individuals within these families. Pairwise LOD scores have been calculated for markers CMM86, NM23, 42D6 and MFD188. The maximal summated LOD for the 15 families is 4.45 at theta = 0.025 using 42D6. All cases of bilateral breast cancer and ovarian cancer appear to be linked to this region. Recalculating LOD scores on the assumption of linkage in these cases increases the maximal summated LOD to 5.62 at theta = 0.025 using 42D6. A genetic exclusion map of critical recombinants in linked families suggests that the gene is flanked by markers 42D6 and MFD188, a region 5 to 10 cm in length.