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Revisiting the complex architecture of ALS in Turkey: Expanding genotypes, shared phenotypes, molecular networks, and a public variant database
Author(s) -
Tunca Ceren,
Şeker Tuncay,
Akçimen Fulya,
Coşkun Cemre,
Bayraktar Elif,
Palvadeau Robin,
Zor Seyit,
Koçoğlu Cemile,
Kartal Ece,
Şen Nesli Ece,
Hamzeiy Hamid,
Özoğuz Erimiş Aslıhan,
Norman Utku,
Karakahya Oğuzhan,
Olgun Gülden,
Akgün Tahsin,
Durmuş Hacer,
Şahin Erdi,
Çakar Arman,
Başar Gürsoy Esra,
Babacan Yıldız Gülsen,
İşak Barış,
Uluç Kayıhan,
Hanağası Haşmet,
Bilgiç Başar,
Turgut Nilda,
Aysal Fikret,
Ertaş Mustafa,
Boz Cavit,
Kotan Dilcan,
İdrisoğlu Halil,
Soysal Aysun,
Uzun Adatepe Nurten,
Akalın Mehmet Ali,
Koç Filiz,
Tan Ersin,
Oflazer Piraye,
Deymeer Feza,
Taştan Öznur,
Çiçek A. Ercüment,
Kavak Erşen,
Parman Yeşim,
Başak A. Nazlı
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24055
Subject(s) - biology , genetics , genome wide association study , exome , penetrance , amyotrophic lateral sclerosis , exome sequencing , locus (genetics) , genetic architecture , population , genome , genetic heterogeneity , gene , disease , genotype , single nucleotide polymorphism , quantitative trait locus , phenotype , demography , pathology , sociology , medicine
The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with ~70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well‐established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome‐wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease‐associated candidates, points to a significant enrichment for cell cycle‐ and division‐related genes. Within this network, literature text‐mining highlights DECR1 , ATL1 , HDAC2 , GEMIN4 , and HNRNPA3 as important genes. Finally, information on ALS‐related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser ( www.gendal.org ).