Table 1.
Segregation analysis and population frequency for exome-sequence variants.
| Variant number | Gene | Chromosome position, hg19 | Protein change | rsid | Top functional categories (pathways//GO biological process) | Expression in GTEX blood/immune samples | Family 6 carriers/cases | Family 8 carriers/cases | Linkage within 20 Mb Family 6 (Z-score) | Linkage within 20 Mb Iceland (Z-score) | Controls | Nordic controls | Maximum MAF in public databases (global population) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | ANKRD50 | chr4:125593332 | T367M | rs140232140 | Transport; protein transport; retrograde transport, endosome to plasma membrane | Yes | 3/8 | — | — | — | 0.0024 | — | 0.0091 |
| 2 | CHD3 | chr17:7810250 | A1523T | rs148451716 | Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3; Chromatin organization; Gene expression//chromatin organization; chromatin assembly or disassembly; transcription, DNA-templated | Yes | 4/8 | — | — | 1.79 | 0 | — | 0.0003 |
| 3 | FAT4 | chr4:126238305 | P247T | rs191329848 | Hippo signaling pathway//branching involved in ureteric bud morphogenesis; kidney development; heart morphogenesis; plasma membrane organization | No | 3/8 | — | — | — | 0.0016 | 0.0061 | 0.0042 |
| 4 | KIR2DS4 | chr19:55358686 | I255L | rs112697729 | Innate immune system; Allograft rejection; Immune response Role of DAP12 receptors in NK cells//innate immune response | Yes | 6/8 | 1/7 | — | 2.06 | 0 | 0.1689 | — |
| 5 | NUP214 | chr9:134027138 | I765V | rs61756081 | HIV Life Cycle; Cell Cycle, Mitotic; Mitotic Prophase; Influenza Viral RNA Transcription and Replication//regulation of glycolytic process; RNA export from nucleus | Yes | 3/8 | — | 1.3 | — | — | 0.012 | 0.0097 |
| 6 | PDHA2 | chr4:96762158 | R286P | rs147966234 | Citrate cycle (TCA cycle); Glucose metabolism; Carbon metabolism//carbohydrate metabolic process; glucose metabolic process | No | 3/8 | — | — | — | 0.0071 | 0.0241 | 0.0091 |
| 7 | SCL25A9 | chr1:48694594 | G103R | rs61746559 | Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds; Hexose transport//transport; ion transport | No | 4/8 | 2/7 | 1.13 | 2.4 | 0.0071 | 0.006 | 0.0525 |
| 8 | XRCC6BP1 | chr12:58350618 | A229V | rs117230607 | Double-strand break repair via nonhomologous end joining; protein phosphorylation; proteolysis | Yes | 6/8 | — | — | — | 0.0063 | 0.0183 | 0.0053 |
| 9 | TPRA1 | chr3:127292588 | E300K | rs372625321 | Lipid metabolic process; G-protein coupled receptor signaling pathway; aging; negative regulation of mitotic cell cycle phase transition | Yes | — | 3/7 | — | — | — | — | 0.00008 |
| 10 | KRTAP4-9 | chr17:39261693 | D18V | rs113059833 | Aging; keratinization; hair cycle | No | 8/8 | 4/7 | — | — | 0 | 0.3765 | 0.1879 |
| 11 | MPHOSPH8 | chr13:20224319 | E499K | rs147594834 | Transcription, DNA-templated; regulation of transcription, DNA-templated; regulation of DNA methylation; negative regulation of transcription, DNA-templated | Yes | — | 3/7 | — | — | 0.008 | — | 0.003 |
| 12 | NOTCH1 | chr9:139404360 | D932N | rs758642073 | Signaling by NOTCH1; HIV life cycle//negative regulation of transcription from RNA polymerase II promoter; angiogenesis; in utero embryonic development; cell fate specification | Yes | — | 5/7 | — | — | 0 | — | 0.0002 |
| 13 | PABPC3 | chr13:25670676 | A114T | rs117014540 | mRNA surveillance pathway; Deadenylation-dependent mRNA decay; RNA transport//mRNA metabolic process | No | — | 3/7 | — | — | 0.0094 | 0.012 | 0.0044 |
| 14 | WDR25 | chr14:100847878 | R206H | rs146976933 | _//_ | Yes | — | 3/7 | — | — | 0.0031 | — | 0.008 |
| 15 | CLC | chr19:40225031 | N65K | rs146776010 | Regulation of T cell anergy; regulation of T cell cytokine production; regulation of activated T cell proliferation | Yes | — | 5/7 | — | 2.06 | 0.0071 | 0.006 | 0.0176 |
| 16 | DCLRE1C | chr10:14970085 | H283N | rs772438042 | DNA Double-Strand Break Repair; Primary immunodeficiency; DNA Damage//telomere maintenance; adaptive immune response; immune system process; DNA repair; double-strand break | Yes | — | 5/7 | 1 | — | 0 | — | 0.000008 |
| 17 | FAM71E1 | chr19:50978724 | L7F | rs185418641 | _//_ | No | — | 4/7 | — | 2.06 | 0.0063 | 0.0061 | 0.0073 |
| 18 | FBXL14 | chr12:1702929 | N102H | rs117331652 | Class I MHC mediated antigen processing and presentation; Innate Immune System//protein polyubiquitination; protein ubiquitination involved in ubiquitin-dependent protein catabolic process; post-translational protein modification | Yes | — | 5/7 | — | — | 0.0055 | — | 0.0049 |
| 19 | FAM8A1 | chr6:17601340 | G234R | rs202036280 | _//_ | Yes | — | 3/7 | — | — | — | — | 0.00005 |
Table 1 shows the results from the segregation analysis for the variants identified by WES as the number of family members who were variant carriers affected with SLE (family 8) or any autoimmune disease (family 6), over the total number of cases in each family. Z-score is indicated for the variants located in regions linked to SLE in Iceland according to ref.27. MAF (minor allelic frequency) of the variants in 642 internal whole-genome sequenced European and 83 Nordic controls. The maximum MAF corresponds to the highest frequency of allele in ExAc, 1000 Genomes and GO-ESP data for global population. Variant numbers correspond to those seen in Fig. 3. Functional annotation is shown according to GeneCards SuperPathways and Gene Ontology top biological process categories. The presence of the particular gene transcripts in GTEX blood/immune samples is marked according to Fig. 3. Additional annotation of the variants shown in Table S3.