scholarly journals A linkage and exome study of multiplex families with bipolar disorder implicates rare coding variants of ANK3 and additional rare alleles at 10q11-q21

2021 ◽  
Vol 46 (2) ◽  
Author(s):  
Claudio Toma ◽  
Alex D. Shaw ◽  
Anna Heath ◽  
Kerrie D. Pierce ◽  
Philip B. Mitchell ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Linkage Analysis ◽  
Rare Variants ◽  
Linkage Signal ◽  
Risk Variants ◽  
Genome Wide ◽  
Whole Exome ◽  
Family Based ◽  
Coding Variants ◽  
Linkage Interval

Background: Bipolar disorder is a highly heritable psychiatric condition for which specific genetic factors remain largely unknown. In the present study, we used combined whole-exome sequencing and linkage analysis to identify risk loci and dissect the contribution of common and rare variants in families with a high density of illness. Methods: Overall, 117 participants from 15 Australian extended families with bipolar disorder (72 with affective disorder, including 50 with bipolar disorder type I or II, 13 with schizoaffective disorder–manic type and 9 with recurrent unipolar disorder) underwent whole-exome sequencing. We performed genome-wide linkage analysis using MERLIN and conditional linkage analysis using LAMP. We assessed the contribution of potentially functional rare variants using a genebased segregation test. Results: We identified a significant linkage peak on chromosome 10q11-q21 (maximal single nucleotide polymorphism = rs10761725; exponential logarithm of the odds [LODexp] = 3.03; empirical p = 0.046). The linkage interval spanned 36 protein-coding genes, including a gene associated with bipolar disorder, ankyrin 3 (ANK3). Conditional linkage analysis showed that common ANK3 risk variants previously identified in genome-wide association studies — or variants in linkage disequilibrium with those variants — did not explain the linkage signal (rs10994397 LOD = 0.63; rs9804190 LOD = 0.04). A family-based segregation test with 34 rare variants from 14 genes under the linkage interval suggested rare variant contributions of 3 brain-expressed genes: NRBF2 (p = 0.005), PCDH15 (p = 0.002) and ANK3 (p = 0.014). Limitations: We did not examine non-coding variants, but they may explain the remaining linkage signal. Conclusion: Combining family-based linkage analysis with next-generation sequencing data is effective for identifying putative disease genes and specific risk variants in complex disorders. We identified rare missense variants in ANK3, PCDH15 and NRBF2 that could confer disease risk, providing valuable targets for functional characterization.

scholarly journals Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yue Wang ◽  
Xuejuan Chen ◽  
Tao Jiang ◽  
Yayun Gu ◽  
Xiaohan Zhang ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Childhood Onset ◽  
Lod Score ◽  
Genome Wide ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
The Family ◽  
Log Odds ◽  
Normal Controls ◽  
Linkage Interval

Abstract Background Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS. Methods Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family. Results Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls. Conclusion LRP2 is a novel candidate genetic cause of non-syndromic familial CS.

scholarly journals Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family

2018 ◽  
Vol 25 (7) ◽  
pp. 909-917 ◽  
Author(s):  
Julia Y Mescheriakova ◽  
Annemieke JMH Verkerk ◽  
Najaf Amin ◽  
André G Uitterlinden ◽  
Cornelia M van Duijn ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Complex Disease ◽  
Rare Variants ◽  
Missense Variant ◽  
Joint Effect ◽  
Genome Wide ◽  
Whole Exome ◽  
Coding Variants

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS. Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations. Methods: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls. Results: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8–2.4), p = 0.31). Conclusion: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.

Family-based exome-sequencing approach identifies rare susceptibility variants for lithium-responsive bipolar disorder

Genome ◽  
2013 ◽  
Vol 56 (10) ◽  
pp. 634-640 ◽  
Author(s):  
Cristiana Cruceanu ◽  
Amirthagowri Ambalavanan ◽  
Dan Spiegelman ◽  
Julie Gauthier ◽  
Ronald G. Lafrenière ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Rare Variants ◽  
Association Studies ◽  
Phenotypic Heterogeneity ◽  
Exome Capture ◽  
Genome Wide Association Studies ◽  
Complex Disorder ◽  
Genome Wide ◽  
High Throughput Dna Sequencing ◽  
Family Based

Bipolar disorder (BD) is a psychiatric condition characterized by the occurrence of at least two episodes of clinically disturbed mood including mania and depression. A vast literature describing BD studies suggests that a strong genetic contribution likely underlies this condition; heritability is estimated to be as high as 80%. Many studies have identified BD susceptibility loci, but because of the genetic and phenotypic heterogeneity observed across individuals, very few loci were subsequently replicated. Research in BD genetics to date has consisted of classical linkage or genome-wide association studies, which have identified candidate genes hypothesized to present common susceptibility variants. Although the observation of such common variants is informative, they can only explain a small fraction of the predicted BD heritability, suggesting a considerable contribution would come from rare and highly penetrant variants. We are seeking to identify such rare variants, and to increase the likelihood of being successful, we aimed to reduce the phenotypic heterogeneity factor by focusing on a well-defined subphenotype of BD: excellent response to lithium monotherapy. Our group has previously shown positive response to lithium therapy clusters in families and has a consistent clinical presentation with minimal comorbidity. To identify such rare variants, we are using a targeted exome capture and high-throughput DNA sequencing approach, and analyzing the entire coding sequences of BD affected individuals from multigenerational families. We are prioritizing rare variants with a frequency of less than 1% in the population that segregate with affected status within each family, as well as being potentially highly penetrant (e.g., protein truncating, missense, or frameshift) or functionally relevant (e.g., 3′UTR, 5′UTR, or splicing). By focusing on rare variants in a familial cohort, we hope to explain a significant portion of the missing heritability in BD, as well as to narrow our current insight on the key biochemical pathways implicated in this complex disorder.

scholarly journals Identification of sixteen novel candidate genes for late onset Parkinson’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Alessandro Gialluisi ◽  
Mafalda Giovanna Reccia ◽  
Nicola Modugno ◽  
Teresa Nutile ◽  
Alessia Lombardi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Candidate Genes ◽  
Rare Variants ◽  
Late Onset ◽  
High Specificity ◽  
Diagnostic Tools ◽  
Multi Stage ◽  
Whole Exome ◽  
Family Based

Abstract Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment.

scholarly journals A family-based association study after genome-wide linkage analysis identified two genetic loci for renal function in a Mongolian population

2013 ◽  
Vol 83 (2) ◽  
pp. 285-292 ◽  
Author(s):  
Hansoo Park ◽  
Hyun-Jin Kim ◽  
Seungbok Lee ◽  
Yun Joo Yoo ◽  
Young Seok Ju ◽  
...  
Keyword(s):  
Renal Function ◽  
Linkage Analysis ◽  
Association Study ◽  
Genetic Loci ◽  
Genome Wide ◽  
Family Based

Abstract 12: Heritability of Ischemic Stroke and its Subtypes

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Andrew E Bluher ◽  
Michael A Nalls ◽  
John W Cole ◽  
Pankaj Sharma ◽  
James F Meschia ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Fixed Effects ◽  
Rare Variants ◽  
Phenotypic Variability ◽  
Fixed Effects Model ◽  
Stroke Subtype ◽  
Genome Wide ◽  
Weighted Means ◽  
Family Based ◽  
And Gender

Background and Purpose: Family-based methods for estimating heritability cannot discriminate between shared genetic and shared environmental exposures. Recently, methods have been developed for estimating heritability in population samples using genome-wide SNPs. We used the approach developed by Visscher and colleagues to estimate the heritability of ischemic stroke in Caucasian subjects. In addition to evaluating the overall heritability of ischemic stroke, we assessed whether stroke heritability varies by age, gender, and stroke subtype. Methods: Using publicly available software (GCTA and PLINK), we estimated ischemic stroke heritability stratified by age and gender using genome-wide association (GWA) data from three Caucasian ischemic stroke studies: Ischemic Stroke Genetics Study (ISGS), Bio-Repository of DNA in Stroke (BRAINS), and Genetics of Early-Onset Stroke (GEOS). Weighted means of site-specific heritability point estimates were combined according to a standard fixed effects model. Results: Conclusions: A SNP-based approach may be useful in discerning differences in ischemic stroke heritability between different cohorts and subtypes. Overall, our analysis estimated ischemic stroke heritability to be 31% (SE = 7%), with a suggestion of higher heritability for younger cases. Small vessel stroke showed the highest heritability (58 ± 19%), with cardioembolic showing the lowest heritability (16 ± 14%). It should be emphasized that heritability estimates are population-specific and that the method used only reflects the heritability captured by common SNP variants measured in GWA studies, and not phenotypic variability explained by rare variants.

scholarly journals Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

2020 ◽  
Vol 9 (6) ◽  
pp. 1851
Author(s):  
Bàrbara Torrico ◽  
Ester Antón-Galindo ◽  
Noèlia Fernàndez-Castillo ◽  
Eva Rojo-Francàs ◽  
Sadaf Ghorbani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Psychiatric Disorders ◽  
Rare Variants ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Risk Variants ◽  
Whole Exome ◽  
Target Binding ◽  
Functional Analyses

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

SMARCA2 common variant association and rare variant excess in Schizophrenia patients from an Algerian Trio Cohort

2011 ◽  
Vol 26 (S2) ◽  
pp. 1346-1346
Author(s):  
D. Benmessaoud ◽  
A.-M. Lepagnol-Bestel ◽  
M. Delepine ◽  
J. Hager ◽  
J.-M. Moalic ◽  
...  
Keyword(s):  
Rare Variants ◽  
Association Studies ◽  
Common Variant ◽  
Genome Wide Association Studies ◽  
Common Variants ◽  
Fisher Test ◽  
Coding Regions ◽  
Genome Wide ◽  
Whole Exome ◽  
Positive Evolution

Genome wide association studies (GWAS) of Schizophrenia (SZ) patients have identified common variants in ten genes including SMARCA2 (Koga et al., HMG, 2009). We found that the SZ-GWAS genes are part of an interacting network centered on SMARCA2 (Loe-Mie et al., HMG, 2010). Furthermore, SMARCA2 was found disrupted in SZ (Walsh et al., Science, 2008). SMARCA2 encodes the ATPase (BRM) of the SWI/SNF chromatin remodeling complex that is at the interface of genome and environmental adaptation.Taking advantage of an Algerian trio cohort of one hundred SZ patients (Benmessaoud et al., BMC Psychiatry, 2008), we replicated the association of SNP rs2296212 localized in exon 33, already shown associated in Koga study and resulting in D1546E amino acid change in the SMARCA2 protein. We studied SMARCA2 codons and found that exon 33 displays a signature of positive evolution in the primate lineage.Our working hypothesis is that the coding regions displaying positive selection are target of novel rare variants. To address this question, we sequenced two exons displaying positive evolution and one exon without evidence of positive evolution.We found (i) that rare variants are significantly in excess in SZ-patients compared to their parents (p = 0.038, Fisher test) and (ii) a higher proportion of rare variants in the primate-accelerated exons compared with the non-evolutionary exon in SZ-patients (p = 0.032, Fisher test).SMARCA2 exon sequencing and whole exome sequencing from patients harboring SNP rs2296212 common variant are under progress. Altogether, these results are expected to give new insights into the genetic architecture of SZ.

scholarly journals Family-based exome sequencing identifies rare coding variants in age-related macular degeneration

2020 ◽  
Vol 29 (12) ◽  
pp. 2022-2034 ◽  
Author(s):  
Rinki Ratnapriya ◽  
İlhan E Acar ◽  
Maartje J Geerlings ◽  
Kari Branham ◽  
Alan Kwong ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Exome Sequencing ◽  
Target Genes ◽  
Rare Variants ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Genome Wide ◽  
Candidate Target ◽  
Coding Variants

Abstract Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.

Mood-incongruent psychosis in bipolar disorder: conditional linkage analysis shows genome-wide suggestive linkage at 1q32.3, 7p13 and 20q13.31

2009 ◽  
Vol 11 (6) ◽  
pp. 610-620 ◽  
Author(s):  
Marian L Hamshere ◽  
Thomas G Schulze ◽  
Johannes Schumacher ◽  
Aiden Corvin ◽  
Michael J Owen ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Linkage Analysis ◽  
Suggestive Linkage ◽  
Genome Wide
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