The Genetics of Atypical Femur Fractures—a Systematic Review

Abstract Purpose of Review Atypical femur fractures (AFFs) are rare subtrochanteric or diaphyseal fractures regarded as side effects of bisphosphonates (BPs), possibly with a genetic background. Here, we summarize the most recent knowledge about genetics of AFFs. Recent Findings AFF has been reported in 57 patients with seven different monogenic bone disorders including hypophosphatasia and osteogenesis imperfecta; 56.1% had never used BPs, while 17.5% were diagnosed with the disorder only after the AFF. Gene mutation finding in familial and sporadic cases identified possible AFF-related variants in the GGPS1 and ATRAID genes respectively. Functional follow-up studies of mutant proteins showed possible roles in AFF. A recent small genome-wide association study on 51 AFF cases did not identify significant hits associated with AFF. Summary Recent findings have strengthened the hypothesis that AFFs have underlying genetic components but more studies are needed in AFF families and larger cohorts of sporadic cases to confirm previous results and/or find novel gene variants involved in the pathogenesis of AFFs.

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Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005753118 ◽

2021 ◽

Vol 118 (12) ◽

pp. e2005753118

Author(s):

Aditya Ambati ◽

Ryan Hillary ◽

Smaranda Leu-Semenescu ◽

Hanna M. Ollila ◽

Ling Lin ◽

...

Keyword(s):

Bipolar Disorder ◽

Genome Wide Association Study ◽

Perinatal Outcomes ◽

Case Control ◽

Risk Scores ◽

Circadian Regulation ◽

Genetic Associations ◽

Imaging Studies ◽

Genome Wide

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

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Genome-Wide Association Study of Prevalent and Persistent Cervical High-Risk Human Papillomavirus(HPV) Infection

10.21203/rs.2.16987/v1 ◽

2019 ◽

Author(s):

Sally N. Adebamowo ◽

Adebowale A Adeyemo ◽

Charles N Rotimi ◽

Olayinka Olaniyan ◽

Richard B. Offiong ◽

...

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Association Study ◽

Genome Wide Association Study ◽

Principal Component ◽

Hpv Infection ◽

Genome Wide Association ◽

Replication Studies ◽

Genome Wide

Abstract Background: Genetic factors may influence the susceptibility to high-risk human papillomavirus (hrHPV) infection and persistence. We conducted the first genome-wide association study (GWAS) to identify variants associated with cervical hrHPV infection and persistence. Methods: Participants were 517 Nigerian women evaluated at baseline and 6 months follow-up visits for HPV. HPV was characterized using SPF10/LiPA25. hrHPV infection was positive if at least one carcinogenic HPV genotype was detected in a sample provided at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected in each of the samples provided at the baseline and follow-up visits. Genotyping was done using the Illumina Multi-Ethnic Genotyping Array (MEGA) and imputation was done using the African Genome Resources Haplotype Reference Panel. Association analysis was done under additive genetic models adjusted for age, HIV status and the first principal component (PC) of the genotypes. Results: The mean (±SD) age of the study participants was 38 (±8) years, 48% were HIV negative, 24% were hrHPV positive and 10% had persistent hrHPV infections. The top three variants associated with hrHPV infections were intronic variants clustered in KLF12 (all OR: 7.06, p=1.43 x 10-6). The top variants associated with cervical hrHPV persistence were in DAP(OR: 6.86, p=7.15 x 10-8), NR5A2(OR: 3.65, p=2.03 x 10-7) and MIR365-2(OR: 7.71, p=2.63 x 10-7) gene regions. Conclusions: This exploratory GWAS yielded novel candidate risk loci for cervical hrHPV infection and persistence. The identified loci have biological annotation and functional data supporting their role in hrHPV infection and persistence. Given our limited sample size, larger discovery and replication studies are warranted to further characterize the reported associations.

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Genome-Wide Association Study for Coronary Artery Calcification With Follow-Up in Myocardial Infarction

Circulation ◽

10.1161/circulationaha.110.974899 ◽

2011 ◽

Vol 124 (25) ◽

pp. 2855-2864 ◽

Cited By ~ 196

Author(s):

Christopher J. O'Donnell ◽

Maryam Kavousi ◽

Albert V. Smith ◽

Sharon L.R. Kardia ◽

Mary F. Feitosa ◽

...

Keyword(s):

Myocardial Infarction ◽

Coronary Artery ◽

Association Study ◽

Coronary Artery Calcification ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide

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Follow-up and Extension of a Prior Genome-wide Association Study of Posttraumatic Stress Disorder: Gene × Environment Associations and Structural Magnetic Resonance Imaging in a Highly Traumatized African-American Civilian Population

Biological Psychiatry ◽

10.1016/j.biopsych.2014.01.017 ◽

2014 ◽

Vol 76 (4) ◽

pp. e3-e4 ◽

Cited By ~ 14

Author(s):

Lynn M. Almli ◽

Amita Srivastava ◽

Negar Fani ◽

Kimberly Kerley ◽

Kristina B. Mercer ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

African American ◽

Genome Wide Association Study ◽

Stress Disorder ◽

Genome Wide Association ◽

Resonance Imaging ◽

Structural Magnetic Resonance Imaging ◽

Gene Environment ◽

Genome Wide

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Discovering missing heritability and early risk prediction for type 2 diabetes: a new perspective for genome-wide association study analysis with the Nurses’ Health Study and the Health Professionals’ Follow-Up Study

TURKISH JOURNAL OF MEDICAL SCIENCES ◽

10.3906/sag-1310-77 ◽

2014 ◽

Vol 44 ◽

pp. 946-954 ◽

Cited By ~ 4

Author(s):

Hüsamettin GÜL ◽

Yeşim AYDIN SON ◽

Cengizhan AÇIKEL

Keyword(s):

Health Professionals ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Health Study ◽

Follow Up Study ◽

Early Risk ◽

Genome Wide ◽

New Perspective

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Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders

The British Journal of Psychiatry ◽

10.1192/bjp.bp.115.168229 ◽

2016 ◽

Vol 209 (3) ◽

pp. 236-243 ◽

Cited By ~ 18

Author(s):

Jonathan R. I. Coleman ◽

Kathryn J. Lester ◽

Robert Keers ◽

Susanna Roberts ◽

Charles Curtis ◽

...

Keyword(s):

Anxiety Disorders ◽

Association Study ◽

Treatment Response ◽

Genome Wide Association Study ◽

Behavioural Therapy ◽

Post Treatment ◽

Genome Wide Association ◽

Genome Wide ◽

Cognitive Behavioural

BackgroundAnxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.AimsTo perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).MethodPresence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.ResultsNo variants passed a genome-wide significance threshold (P=5×10–8) in either analysis. Four variants met criteria for suggestive significance (P<5×10–6) in association with response post-treatment, and three variants in the 6-month follow-up analysis.ConclusionsThis is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

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Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CLBL genes

Multiple Sclerosis Journal ◽

10.1177/1352458511432741 ◽

2011 ◽

Vol 18 (7) ◽

pp. 959-965 ◽

Cited By ~ 20

Author(s):

Jezabel Varadé ◽

Manuel Comabella ◽

Miguel A Ortiz ◽

Rafael Arroyo ◽

Oscar Fernández ◽

...

Keyword(s):

Multiple Sclerosis ◽

Autoimmune Diseases ◽

Association Study ◽

Genome Wide Association Study ◽

Susceptibility Gene ◽

Pooled Analysis ◽

Replication Study ◽

Genome Wide Association ◽

Genome Wide

Background and objectives: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate. Methods: Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls. Results: Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353). Conclusions: Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: pM-H=0.001; ORM-H (95% CI)= 0.84 (0.75–0.93)], IL12B [rs6887695: pM-H=0.03; ORM-H (95% CI)= 1.09 (1.01–1.17)] and CBLB [rs9657904: pM-H=0.01; ORM-H (95% CI)= 0.89 (0.81–0.97)].

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

10.1101/821652 ◽

2019 ◽

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL-region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, several functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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Genomic and functional gene studies suggest a key role of beta-carotene oxygenase 1 like (bco1l) gene in salmon flesh color

Scientific Reports ◽

10.1038/s41598-019-56438-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Hanna Helgeland ◽

Marte Sodeland ◽

Nina Zoric ◽

Jacob Seilø Torgersen ◽

Fabian Grammes ◽

...

Keyword(s):

Genome Wide Association Study ◽

Beta Carotene ◽

Color Variation ◽

Flesh Color ◽

Functional Studies ◽

Genetic Components ◽

Genome Wide ◽

A Genome ◽

Mrna And Protein Expression

AbstractRed coloration of muscle tissue (flesh) is a unique trait in several salmonid genera, including Atlantic salmon. The color results from dietary carotenoids deposited in the flesh, whereas the color intensity is affected both by diet and genetic components. Herein we report on a genome-wide association study (GWAS) to identify genetic variation underlying this trait. Two SNPs on ssa26 showed strong associations to the flesh color in salmon. Two genes known to be involved in carotenoid metabolism were located in this QTL- region: beta-carotene oxygenase 1 (bco1) and beta-carotene oxygenase 1 like (bco1l). To determine whether flesh color variation is caused by one, or both, of these genes, functional studies were carried out including mRNA and protein expression in fish with red and pale flesh color. The catalytic abilities of these two genes were also tested with different carotenoids. Our results suggest bco1l to be the most likely gene to explain the flesh color variation observed in this population.

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